doi: 10.1161/CIRCRESAHA.107.165324
© 2008 American Heart Association, Inc.
Review |
The Sulfonylurea Receptor, an Atypical ATP-Binding Cassette Protein, and Its Regulation of the KATP Channel
From the Division of Cardiology, Feinberg Cardiovascular Institute, Northwestern University, Chicago, Ill.
Correspondence to Hossein Ardehali, MD, PhD, Tarry 12-725, 303 E Chicago Ave, Chicago, IL 60611. E-mail h-ardehali{at}northwestern.edu
This Review is part of a thematic series on ABC Transporters in the Cardiovascular System, which includes the following articles:
ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease
The Sulfonylurea Receptor, an Atypical ATP-Binding Cassette Protein, and Its Regulation of the KATP Channel
Jack F. Oram Guest Editor
 |
Abstract |
|---|
 Top Abstract IntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
ATP-binding cassette (ABC) proteins are highly conserved and widely expressed throughout nature and found in all organisms, both prokaryotic and eukaryotic. They mediate myriad critical cellular processes, from nutrient import to toxin efflux using the energy derived from ATP hydrolysis. Most ABC proteins mediate transport of substances across lipid membranes. However, there are atypical ABC proteins that mediate other processes. These include, but are not limited to, DNA repair (bacterial MutS), ion transport (cystic fibrosis transmembrane receptor), and mRNA trafficking (yeast Elf1p). The sulfonylurea receptor (SUR) is another atypical ABC protein that regulates activity of the potassium ATP channel (KATP). KATP is widely expressed in nearly all tissues of higher organisms and couples cellular energy status to membrane potential. KATP is particularly important in the regulation of insulin secretion from pancreatic β-cells and in regulating action potential duration in muscle cells. SUR is indispensable for normal channel function, and mutations in genes encoding SURs increase the susceptibility to diabetes, myocardial infarction, and heart failure. Here, we review the structure and function of ABC proteins and discuss SUR, its regulation of the KATP channel, and its role in cardiovascular disease.
Key Words: sulfonylurea receptor • SUR2 • ATP-binding cassette (ABC) protein • KATPmyocardium
|
Introduction |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
ATP-binding cassette (ABC) proteins constitute one of the largest and most diverse families of proteins. ABC proteins use the energy derived from ATP hydrolysis to mediate their actions, usually transport of molecules across lipid bilayers. Presently, there are
6000 known ABC proteins; they are found in all cells, from bacteria to humans, and are highly conserved.1 Expression is highly variable across species, with humans having only 48 known ABC genes2 compared with E coli, which has 79 ABC genes, making up a remarkable 5% of the genome.3 ABC proteins serve 3 major functions within cells: import of molecules, export of molecules, and regulation of intracellular processes. ABC proteins, which mediate the first 2 of these functions, are sometimes referred to as traffic ABC proteins. ABC importers are only found in prokaryotes, where they play a critical role in bringing essential nutrients into cells. Eukaryotes have evolved other forms of nutrient acquisition and, as a result, do not contain any known ABC importers. ABC exporters are found in both prokaryotes and eukaryotes and serve many functions. In prokaryotes, the most clinically significant function of exporters is to mediate the efflux of toxins such as antibiotics via the prokaryotic transporter MsbA and other associated ABC proteins.4 This function underlies the development of antimicrobial resistance in bacteria and represents one of the greatest challenges to modern medicine. Similarly, ABC transporters mediate antimicrobial resistance in both fungi5 and yeast.6 In plants, ABC proteins play a role in developmental processes,7 regulation of growth and function via vacuolar transport of molecules within the cell,8 removal of toxins such as herbicides,9 and transport of molecules that regulate plant responses to environmental stressors such as microbial pathogens, herbivores, and UV radiation.10 In animals, ABC transporters play a role in many important physiological processes. In humans, these include, but are not limited to, cholesterol transport,11 antigen presentation to T cells,12 cellular iron trafficking,13 bile acid transport,14 and maintenance of the blood–brain barrier.15 In prokaryotes, nearly all ABC transporters are found in the plasma membrane. Interestingly, eukaryotic ABC transporters are located in the plasma membrane as well as in the membranes of peroxisomes, lysosomes, vacuoles, endosomes, the Golgi apparatus, the endoplasmic reticulum (ER), and the mitochondria.16 For instance, ABCA5 localizes to the lysosomal membrane and, although the normal physiological function remains unknown, ABCA5 knockout (KO) mice develop a dilated cardiomyopathy with associated congestive heart failure, a phenotype similar to other forms of lysosomal diseases.17 The mitochondrial ABC transporter mABC1 has been identified recently as a component of a mitochondrial structure with KATP channel activity and has been shown to be cytoprotective in the face of oxidative stress in neonatal rat cardiomyocytes.18,19 Another mitochondrial protein, MTABC3, a product of the ABCB6 gene, plays a key role in heme biosynthesis via transport of mitochondrial porphyrins.20 Adrenoleukodystrophy results from abnormal accumulation of very long chain fatty acids, resulting from impaired β-oxidation in peroxisomes. This disease has been linked to mutations in the protein ALD, a product of the ABCD1 gene; however, its pathophysiological role in adrenoleukodystrophy is not yet known.21
Here, we review the structure and function of SUR as a model of ABC function and review its role in cardiovascular disease. An additional article in this review series focuses on the role of ABC transporters in the processing and trafficking of cholesterol in the cardiovascular system.
|
ABC Proteins and Human Disease |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
Given the diverse and important roles of ABC proteins, and their divergent subcellular locations, it is no surprise that mutations in ABC genes lead to a number of clinically important disease states.22 The prototypical human disease caused by a mutant ABC protein is cystic fibrosis.23 Cystic fibrosis is caused by mutations in the CFTR gene (also known as ABCC7). CFTR is unique in that it is the only ion channel in the ABC family. Decreased function of CFTR makes the affected membranes essentially impermeable to chloride ions, resulting in the diseased phenotype.24 Recently, Tangier disease, a rare disorder characterized by abnormal, diffuse cholesterol deposition and accelerated atherosclerosis, has been shown to be attributable to a mutation in the ABCA1 gene.25–27 This gene is critical for the normal production of mature high-density lipoprotein (HDL) particles. Mutations in ABCA1 also cause familial HDL deficiency (reviewed in detail elsewhere28). Other disorders associated with mutations in ABC proteins include Dubin–Johnson syndrome and other inherited diseases of bile transport,14,29,30 adrenoleukodystrophy,31 surfactant deficiency and other pulmonary disorders,32,33 lamellar ichthyosis,34 immunodeficiency,35 DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome,36 and X-linked sideroblastic anemia with ataxia (Table 1).37,38 P-Glycoprotein (PGY1), also known as the human multidrug resistance protein (MDR1), is a product of the ABCB1 gene that is widely distributed and mediates toxin efflux out of mammalian cells. PGY1 plays a major role in the resistance to chemotherapeutic agents39 and also likely plays a role in the efflux of immunosuppressants in posttransplantation patients, contributing to clinically observed variations in organ rejection.40
|
There are many ABC transporters expressed in the heart, and they are becoming more appreciated for their role in cardiac physiology and disease.41 As mentioned previously, ABCA5 KO mice develop dilated cardiomyopathy.17 ABCG2 is expressed in cardiac vascular endothelium and is upregulated in ischemic and nonischemic dilated cardiomyopathy, although its function is not known.42 PGY1 is not normally expressed in the myocardium but has been shown to be expressed in myocytes exposed to both acute ischemia/reperfusion43 and chronic ischemia.44 MRP1, a product of the ABCC1 gene, is upregulated in mouse hearts after treatment with the cardiotoxic chemotherapeutic agent doxorubicin, suggesting a possible protective role in the myocardium.45 Interestingly, MRP1 is also upregulated in the myocardium in response to acute and chronic exercise in rats and may play a role in cardioprotection against acute and chronic oxidative stress.46 Dystrophic cardiac calcification, an uncommon disorder that is occasionally a long-term complication of myocardial infarction, is caused by mutations in the ABCC6 gene.47 Perhaps the most widely studied ABC proteins in myocardial disease are those that regulate cholesterol transport (ABCA1, ABCG1, ABCG5, and ABCG8)48 and the sulfonylurea receptor, which is an atypical ABC protein that is part of the sarcolemmal potassium ATP (KATP) channel.
|
Structure of ABC Proteins |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
Typical ABC Proteins
A typical ABC protein contains 4 domains, 2 nucleotide-binding domains (NBDs) (also referred to as ABC domains), and 2 transmembrane domains (TMDs).49 Domains can be encoded as separate polypeptides (most common in prokaryotes), dimers, trimers, or complete proteins.50 The TMDs are highly hydrophobic, and each contains 6 membrane-spanning segments. These domains form the pore through which substrates cross and are also believed to determine substrate specificity (Figure 1).16 This is illustrated by the crystal structure of the bacterial FhuA protein, which forms a transmembrane pore that is covered by a hydrophilic plug; this plug moves upon binding of ferrichrome, the ligand transported by this protein.51 Further crystal structures of other bacterial ABC proteins show varying pore conformations and additional gating mechanisms based on substrate specificity.52–54
|
The ABC domains are hydrophilic and are present at the cytoplasmic aspect of the membrane. These domains consist of 215 amino acids (aa), are highly conserved throughout evolution, and can bind to and hydrolyze ATP. The ABC domains contain 3 major conserved motifs: the Walker A and Walker B domains, which are necessary for binding of ATP, and the signature, or linker motif (also known as the C region), LSGGQ.50 The ABC domain is the defining feature of the ABC family of proteins, and its presence is used to identify new members of this class of molecules.55 Although most ABC proteins contain 2 ABC and 2 TMD, there are half-ABC proteins containing only 1 of each domain. These half-proteins can exist as either homo- or heterodimers. Numerous crystal structures have shown that the 2 ABC domains dimerize such that they are antiparallel in organization with the conserved Walker A site of 1 NBD aligning with the conserved linker motif of the opposite NBD.53,54,56 The configuration of the NBDs is critical for normal function, and crystal structures have shown the location of many mutations in the NBDs that cause cystic fibrosis, suggesting the possible mechanistic flaw associated with particular CFTR mutations.56,57
In addition to these core domains, there is a wide variety of accessory components that play key roles in the function of specific ABC transporters.58 Many accessory components are proteins that transport the substrates to the ABC transporters. These accessory proteins are highly specific and are structurally altered by binding with the ABC transporter.54 Not surprisingly, these accessory components also induce structural changes in the associated ABC transporter that facilitate transport.59 These accessory proteins add yet another layer of diversity to the family of ABC transporters.
Atypical ABC Proteins
Although the majority of ABC proteins directly transport molecules across membranes, there are several ABC proteins that are not involved in substrate transport and are referred to as "atypical" ABC proteins (Table 2).50 These proteins, which clearly do not mediate transport, are classified as ABC proteins because of the presence of the highly conserved ABC domain. Interestingly, many of these atypical ABC proteins have been modified to bind nucleic acids. A classic example of an atypical ABC protein is the bacterial UvrA, which functions in UV-induced DNA repair.60 MutS is another bacterial ABC protein, which plays a critical role in DNA mismatch repair.61 MutS contains the highly conserved ABC motif and forms homo- or heterodimers for function, whereas the transmembrane domain has essentially been replaced by structural motifs involved in the recognition and binding of DNA.61 Similarly, Rad50 contains conserved ABC domains and regulates DNA double-strand break repair. Rad50 also requires dimerization with a total of 4 domains, 2 DNA-binding domains and 2 ABC domains, for normal function.62 The SMC (structural maintenance of chromosomes) proteins are another class of molecules that contain the classic ABC motif and also bind DNA.63 SMC proteins are highly conserved from bacteria to humans and play a critical role in the organization of chromosomes; their role as dynamic ATPases is only beginning to be appreciated.63 The yeast protein Elf1p is also an ABC protein and plays a direct role in the transport of mRNA from the nucleus to the cytoplasm, although whether or not Elf1p binds RNA is still unclear.64
|
In addition to DNA binding, atypical ABC proteins perform other functions. The eukaryotic elongation factor 3 (eEF3) is an ABC protein that plays a key regulatory role in translation.65 As mentioned, SUR is another atypical ABC protein. SUR associates with one of the Kir6.x potassium channel subunits to form ATP-sensitive potassium channels (KATP).66 This represents a unique function among the ABC family of proteins. Unlike other atypical ABC proteins, SUR has maintained its transmembrane domain but is not thought to be directly involved in the transport of molecules across the membrane. In recent years, KATP channels have become increasingly recognized for their importance in both diabetes and cardiovascular diseases. These channels are an active area of research and are the targets of several different drugs.
|
The KATP Channel: Structure and Function |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
The KATP channel serves as a sensor of the cellular metabolic state and couples the metabolism of the cell with the membrane potential, primarily by sensing intracellular ATP levels.67 It is an octamer composed of 4 Kir6 subunits and 4 SUR subunits (Figure 2A).67 The Kir6 subunits regulate transport of potassium, whereas the SUR subunits play a regulatory role, modulating channel activity depending on cellular ATP levels. Kir6 is a member of the inwardly-rectifying family of K+ channels. Two Kir6 isoforms exist, Kir6.1 and Kir6.2, both of which are expressed in the heart, with Kir6.2 being the predominant form in the sarcolemma. SUR is an atypical ABC protein that binds to Kir6 subunits to form functional KATP channels.68 There are two SUR isoforms, SUR1 and SUR2, the latter of which has two major splice variants, SUR2A and SUR2B.67,69 In mice, there also have been 2 additional splice variants described. The first encodes a transcript without exon 14 and is only found in the heart.70 The second is characterized by splicing of exon 17, which encodes a region next to the Walker A site of NBD1 and alters channel gating.71 SUR1 and –2 are the products of the ABCC8 and ABCC9 genes, respectively. SUR2A is highly expressed in cardiac tissue, whereas SUR1 is most abundantly expressed in the brain and pancreas (Table 3).72 SUR2B is expressed in vascular smooth muscle cells.72 SUR1 and SUR2 are full ABC proteins, containing 2 TMD and 2 ABC domains. Similar to other ABC proteins including PGY1 and CFTR, SUR also has an additional 5-helix transmembrane domain termed TMD0 that is connected to the remainder of the SUR subunit by a linker region, L0 (Figure 2).73 The TMD0 and L0 regions are able to regulate KATP channel opening, thus suggesting a close functional and physical interaction.74,75 Coimmunoprecipitation studies have demonstrated a tight association between TMD0 and Kir6.76 A 3D model of SUR1/Kir6.2 obtained by single-particle electron microscopy confirms this finding, showing that TMD0 is likely in close association with the outer transmembrane helix of Kir6.2 and L0 is likely in close association with the N terminus of Kir6.2.77 The current working model suggests that the Kir6.x subunits, which constitute the pore of KATP, are located centrally, whereas the SUR subunits are located peripherally, with the important TMD0 domain situated adjacent to the associated Kir6.2 subunit (Figure 2B).73 A crystal structure of the KATP channel is needed for better understanding of the structure and function of the KATP channel.
|
|
The binding of SUR to Kir subunits serves a dual purpose. First, this binding allows translocation of the channel to the plasma membrane. The KATP channel has a remarkably intricate network of internal targeting signals. These targeting signals regulate proper ER trafficking of the KATP channel subunits. There are retrograde signals that block ER export and are present in both the Kir and SUR subunits. These signals are blocked on proper dimerization with the respective subunits.78 Lack of interaction between Kir and SUR results in retention within the ER, and 1:1 subunit stoichiometry is required for cell surface expression.78 In addition, there is also an antegrade-targeting signal in the C terminus of SUR that is required for release from the ER/Golgi and resultant plasma membrane expression.79 Second, the interaction between SUR and Kir subunits contributes to the regulation of the channel itself. Specifically, the binding and hydrolysis of ATP at the canonical NBDs of SUR regulates potassium channel activity. Based on data garnered from bacterial ABC proteins, the NBDs dimerize when bound to nucleotides, facilitating hydrolysis in a cooperative fashion.80 Binding of ADP induces a conformational change in the structure of the ABC proteins that likely regulates protein function.57 Direct evidence for this process is lacking for SUR, but circumstantial data, the SUR1/Kir 3D model, and mutational studies indicate that the NBDs of SUR likely dimerize as well.73,77,81 ATP can also inhibit KATP channel activity by binding to the Kir subunits.73 This tonic inhibition at the Kir subunit is counteracted by Mg2+-bound nucleotide binding at the SUR NBDs.
Although the exact mechanism by which SUR regulates Kir6 is not known, it is generally felt to be attributable to a conformational change in SUR induced by cellular ATP turnover. In other ABC proteins, this conformational change is directly linked to transport across the membrane, whereas in SUR, it is thought to regulate Kir6. SUR, as previously mentioned, interacts with Kir6 via the TMD0 domain and L0,82,83 and recent evidence suggests that binding of ATP to the NBDs mediates a conformational change in the TMD0/L0 region.84 A potential model for this interaction is shown in Figure 2B and 2C. By coupling membrane excitation to the metabolic state of the cell, these channels play key roles in various tissues.
|
The KATP Channel: Physiological and Pathophysiological Functions of SUR1 |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
The KATP channel plays distinct and important physiological roles in several metabolically active tissues, including the pancreas, brain, and muscle. The KATP channel is best characterized in the pancreas, where it is composed of SUR1 and Kir6.2 subunits and plays a prominent role in regulating insulin secretion in the β-cells.85,86 The KATP channel is also expressed in other cells of the endocrine pancreas, including the glucagon-secreting
-cells87 and the somatostatin-secreting 
-cells.88 In pancreatic β-cells, high levels of ATP, corresponding to increased plasma glucose levels, result in KATP channel closure. This closure leads to membrane depolarization, Ca2+ influx, and subsequent insulin release (Figure 3A). Binding of ATP to Kir6.2 subunits mediates this inhibition, and SUR1 markedly potentiates this effect.86 Sulfonylureas, which bind to SURs, are a class of antidiabetic drugs widely used in the treatment of type 2 diabetes mellitus. These drugs bind to the SUR subunit in multiple locations and inhibit KATP channel activity, thus increasing insulin release.89 In the brain, KATP channels are expressed in various regions and seem to play a role in seizure prevention. They also function as centrally acting glucose sensors.67 Further, these channels may also play a role in neuronal ischemic preconditioning, similar to what has been observed in cardiac muscle,90 as described in more detail below.
|
Mutations affecting the KATP channel result in several disease states that alter pancreatic β-cell function. Many of these mutations are found in the SUR1 subunits of pancreatic KATP channels. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder caused by mutations in several genes, including ABCC8, the gene for SUR1.91 PHHI is characterized by inappropriately high levels of insulin secretion despite severe hypoglycemia. Mild cases are readily treatable, although severe forms can be lethal and may require subtotal pancreatectomy.67 There are numerous ABCC8/SUR1 mutations, and they generally fall into two groups. Some mutations prevent trafficking of the KATP channel to the plasma membrane, likely because of inappropriate exposure of the previously mentioned trafficking signals.92,93 Other mutations result in a permanently closed channel that is insensitive to the normal effects of nucleotide binding.91 Both types of mutations lead to a lack of KATP channel activity, which results in constant calcium influx and hence continuous, inappropriate insulin secretion.
There are also mutations of the SUR1 subunit that result in continuous activation of the channel. Transient neonatal diabetes (TND) and permanent neonatal diabetes (PND) are disorders characterized by onset of mild to severe hyperglycemia in the first few months after birth. These disorders are at different ends on the same spectrum of disease and, depending on the mutation and the corresponding increase in function, can be transient or persistent, requiring lifelong treatment.94 Despite the early transient nature of TND, this disease can relapse by the time of adolescence in 50% of patients with certain types of mutations.95 There are several genes associated with this disorder, but recent work has shown numerous activating mutations within the ABCC8 gene, encoding SUR1, that result in either phenotype.96,97 All of these mutations have the common pathophysiology of permanent activation of the KATP channel, resulting in membrane hyperpolarization, reduced calcium influx, and reduced insulin secretion.
The recent spate of genome-wide association studies has shown a strong link between the E23K polymorphism of KCNJ11, the gene encoding Kir6.2, and diabetes.98 Presently, there are no genome-wide association studies linking ABCC8/SUR1 to diabetes. However, there is significant linkage disequilibrium between the KCNJ11 E23K polymorphism and a common polymorphism in ABCC8, A1369S.99 In fact, these 2 polymorphisms are almost always found together and seem to be protective of progression to diabetes in patients enrolled in the Diabetes Prevention Program. These patients all had impaired glucose tolerance at baseline, and the authors suggest that KCNJ11 E23K polymorphism may function at an earlier stage, namely in the development of impaired glucose tolerance.99
|
The KATP Channel: Physiological and Pathophysiological Functions of SUR2 |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
KATP channels in the heart play important roles in cardiac homeostasis. SUR2A is predominantly expressed in the myocardium, whereas SUR2B is predominantly found in the vascular smooth muscle. This tissue-specific distribution has important functional consequences, and the regulation of KATP channels by SUR2x is dependent on subcellular concentrations of high-energy phosphates, as well as structural differences between the two SUR2 subtypes.
SUR2A Regulates KATP by Nucleotide Catalysis and Is a Key Sensor of Cellular Energy Status
As previously mentioned, SUR contains 2 NBDs, which likely work in concert to regulate KATP channel activity.49,100 KATP channels in the pancreas are usually in the open conformation, whereas KATP channels in the myocardium are in the closed state under normal conditions.101 This crucial physiological difference is regulated by the different subtypes of SUR in each tissue.102 In all SUR subtypes, both NBDs are responsible for nucleotide binding, whereas NBD2 carries out ATP hydrolysis.103 However, SUR1 and SUR2A have markedly different binding affinities for ATP and ADP, which is believed to result, at least in part, in their opposite effects on KATP channel gating in these 2 tissues.103 For SUR1, the binding affinities of NBD1 for ATP and ADP, expressed as Ki values, are 4.4 and 26 µmol/L, respectively. For the NBD2 of SUR1, the Ki values for ATP and ADP are 60 and 100 µmol/L, respectively. SUR2A has much lower nucleotide affinity, as shown by higher Ki values: at NBD1, the Ki values for ATP and ADP are 110 and 86 µmol/L, respectively, whereas at NBD2, they are 120 and 170 µmol/L, respectively. The NBDs of SUR2B have nucleotide affinities similar to those of SUR1 (Ki values at NBD1 for ATP and ADP of 51 and 66 µmol/L, and at NBD2, of 38 and 67 µmol/L, respectively).103 These data show that the binding affinities of NBD1 are much lower for SUR2 isoforms than SUR1 and that the SUR2A isoform has a much lower nucleotide-binding affinity than either SUR1 or SUR2B. Additional evidence suggests that the binding of Mg2+ to these nucleotides is critical for nucleotide hydrolysis at NBD2 and for proper channel gating.103,104
The high-affinity SUR1 readily responds to increased intracellular ATP secondary to a rise in glucose. This results in hydrolysis of MgATP to MgADP at NBD2. It is this binding of MgADP to NBD2 that induces the proposed conformational change in SUR, leading to increased channel activity. Because of the high levels of ATP and the high affinity for ATP at NBD2 of SUR1, there is continuous cycling, consequent release of ADP, and KATP channel closure, leading to release of insulin as described previously. In the myocardium, however, the KATP channel is closed under normal conditions, partly because of the typically high ATP content of this tissue. However, under states of stress, cellular ADP levels rise. As ADP levels rise, the NBD2 of SUR2A becomes fixed in the post-hydrolytic state and is bound to MgADP, resulting in decreased ATP cycling at NBD2 and consequent channel opening (Figure 3B).105 The lower nucleotide affinity at NBD2 of SUR2A likely decreases the propensity for ATP to displace ADP from NBD2, thus allowing NBD2 to remain bound to ADP and facilitate channel opening. Normally, ADP levels are as much as 50-fold lower than ATP levels, even under states of significant metabolic stress.67 As such, it is possible that the reduced affinity of SUR2A for ATP plays a significant role in the response of myocardial KATP channels to small but significant changes in ADP levels. In addition to this, SUR1 is a more efficient ATPase than is SUR2A,102 although it is unclear how much the variable nucleotide affinities for the 2 NBDs influence enzymatic activity. The common denominator of channel gating by SUR appears to be MgADP binding to and stimulating channel activity, despite much higher levels of cellular ATP.
How can such minor changes in ADP be capable of regulating channel activity in the presence of such overwhelming amounts of ATP? The energy-sensing system of cardiac cells is found focally throughout the cell and, at the sarcolemma, is composed of KATP, along with several other enzymes of the phosphotransfer system.106 This energy "compartmentalization" allows the energy-sensing system, which includes KATP, to sense minor fluctuations in cellular energy status even when there are not significant total changes in cellular ATP levels.106 This microenvironment allows KATP to be in close association with enzymes such as creatine kinase (CK), adenylate kinase (AK), the muscle form of lactate dehydrogenase (m-LDH) and pyruvate kinase (PK).106 AK is an essential part of intracellular metabolic networks, and it directly regulates the KATP channel response to dynamic stress by transmitting signals from the mitochondria to the surface KATP channel.107 Treatment of cells with oligomycin, a mitochondrial F1/F0 ATP synthase inhibitor, prevents KATP channel opening, providing evidence for this link.107 AK physically associates with KATP, having been detected by both immunoblotting and by measurement of AK activity in KATP immunoprecipitates with a Kir6.2 antibody.107 The m-LDH is also physically associated with KATP and is necessary for the KATP-mediated cytoprotection from ischemia.108 CK, a major scavenger of free ATPase products, also transduces signals to this subsarcolemmal compartment, where it is found in high concentration.109 Like AK, CK has been shown to physically associate with KATP in cardiomyocytes, and it has been shown to specifically associate with the SUR2A subunit but not with the Kir subunits.110 In intact hearts, hypoxia has been shown to reduce CK flux.109 This results in a reduction of the normal transfer of ATP to the subsarcolemmal compartment by CK, leading to locally higher ADP concentrations. This reduced flux therefore compromises removal of ADP from SUR2A NBD2 and hence reduces nucleotide cycling, leading to opening of the channel.109 Both AK isoform 1 KO mice and CK KO mice demonstrate markedly reduced KATP channel gating in response to changes in cellular energy status.107,109 Thus, phosphotransfer reactions are another important means of regulating KATP channel activity and transducing the changes in cellular energy status to KATP channels.
The cycling of nucleotides, in particular the presence of MgADP at NBD2, likely results in a conformational change that causes channel gating. As mentioned previously, it is felt that this conformational change acts through the TMD0/L0 domain, whereby binding of MgADP at NBD2 overrides the inhibition of ATP on Kir6.2; however, this has not been proven directly.73 There is also limited evidence that TMD0/L0 plays a role in the differential gating patterns between SUR2A and SUR1.111 More evidence is needed to better elucidate the role of the SUR2A TMD0/L0 domain on KATP channel function.
In addition to this regulation by SUR2A, KATP channel activity is also influenced by the higher ATP content of myocardial tissue and the direct, noncatalytic inhibition of Kir6.2 by ATP. Thus gating of the KATP channel is attributable to a complex interplay among SUR subtype, SUR NBD nucleotide affinity and hydrolysis, Kir6.2 nucleotide binding, underlying cellular metabolism, and subcellular energy compartmentalization.
SUR2A and SUR2B Have a Variable C Terminus
SUR2B is a splice variant of the ABCC9 gene.72 The only difference between SUR2A and SUR2B is the use of a different exon at the C terminus such that the proteins are identical except for the C-terminal 42 aa.72 Despite this minimal difference, there is a significant difference in channel activity between these 2 subtypes. The C-terminal 42 aa of SUR2B are similar to SUR1. SUR2B mRNA is expressed ubiquitously.69 SUR2B mRNA is the predominant isoform expressed in vascular smooth muscle, where its protein product interacts with Kir6.1, whereas in other forms of smooth muscle, SUR2B associates with Kir6.2. SUR2B has a nucleotide affinity that is much greater than SUR2A and shows channel gating activity similar to that of SUR1.103,112 Structural analysis suggests that the SUR2B C terminus actually interacts with the NBDs, thus regulating the conformational change associated with nucleotide binding.113 When SUR is coexpressed with Kir6.2 in HEK cells, the C terminus of SUR2A appears to have an inhibitory effect on NBD2 MgADP-induced channel activation.114 Replacing the C-terminal 42 aa of SUR1 or SUR2B with that of SUR2A results in reduced MgADP-dependent channel activity, similar to what is seen with functional SUR2A.114 Further research has narrowed the critical regulatory region to a 7-aa sequence within this C terminus.115 More research is needed to fully define the mechanistic differences caused by this altered C terminus.
KATP Channels and Cardioprotection
As mentioned, myocardial KATP channels are closed under normal physiological conditions.101 However, these channels open at the time of a metabolic insult, reducing cardiac excitability and protecting the myocardium against damage. This occurs by a reduction in action potential duration, which leads to decreased Ca2+ flux. This decreases contraction and therefore reduces the consumption of cellular ATP stores.116 The sarcolemmal KATP channel may play a significant role in the process of ischemic preconditioning (IPC), the phenomenon whereby a previous, brief ischemic event results in subsequent protection against a later, more severe ischemic event.117 IPC induces alterations in cellular bioenergetics that preserve myocardial function; this effect is lost in Kir6.2 KO mice, indicating that KATP channels play a role in myocardial protection mediated by IPC.118 Furthermore, KATP channels are vital in the myocardial response to stress, and in either Kir6 KO models or models overexpressing dominant negative Kir6 subunits, there is a blunted adaptive response to stress, resulting in heart failure and other cardiac defects.119–121 Altered calcium handling, resulting from excessive calcium influx that is not properly balanced to the cellular energy supply, is a central feature of this blunted response to IPC and the resulting cardiac defects in response to stress.120,122
Interestingly, recent data show that SUR2 KO mice still exhibit cardioprotection in response to adrenergic stress.123 In fact, SUR2 KO mice actually have been shown to have significantly reduced infarct size and better left ventricular developed pressure compared with wild-type controls in response to ischemia/reperfusion.123 These data indicate that the complete, canonical Kir6.2-SUR2A sarcolemmal KATP channels are not required for cardioprotection as suggested by the Kir6 KO data. An additional finding was that the calcium channel blocker nifedipine blunts this protective response in SUR2 KO mice.123 Therefore, it seems that altered calcium handling is a common underlying feature of these models; however, the increased calcium in this case would seem to be having beneficial effects. These data make it clear that there is much yet to be elucidated regarding the underlying pathways of IPC.
Indeed, although sarcolemmal KATP channels clearly regulate myocardial response to stress and likely play a role in IPC, there are many other mediators of this process.124 Recent evidence shows that KATP channel recruitment and activity is regulated by the AMP activated protein kinase (AMPK), itself a key mediator of cellular metabolic status.125 Furthermore, sarcolemmal KATP is not the only potassium channel to regulate ischemic preconditioning. Recently, the mitochondrial KATP (mitoKATP) channel has been shown to play a role in ischemic preconditioning, independent of sarcolemmal KATP.126 This channel is reviewed elsewhere,126 but it is interesting to note that mitoKATP is believed to be composed of several proteins, 1 of which is mABC1,18 an ABC protein whose role in this complex is not known but whose overexpression is protective against oxidant stress in neonatal rat cardiomyocytes.19 Another layer of complexity regarding the role of KATP in IPC has been added by the recent finding that SUR2A is expressed not only in the sarcolemma but also the mitochondria of cardiomyocytes.127 It remains to be seen whether functional SUR-containing KATP channels will be found in the mitochondria and, if so, what role they play in IPC or general cardiac cellular physiology.
SUR Subunits Respond Differently to Pharmacotherapeutic Agents That Regulate KATP Channels
KATP channels are targets of many different pharmacological compounds, including both inhibitors of channel activity and activators of channel activity. Many of these drugs act through the SUR subunit. The best-known drugs that regulate KATP channels are the sulfonylureas. Sulfonylureas are widely used to treat type 2 diabetes mellitus, acting as insulin secretagogues by inducing β-cell KATP channel closure on binding to SUR1.89 Different molecules within this class have different binding affinities for SUR subtypes, with some being very specific for SUR1 (eg, nateglinide, mitiglinide), some being moderately specific for SUR1 (eg, glyburide, glimepiride), and others being essentially not selective (eg, repaglinide).128 Given this spectrum of specificity, it would be expected that some sulfonylureas have adverse cardiac effects by preventing the protective effects of IPC because of their ability to close KATP channels, and at least one of these, repaglinide, lists "myocardial ischemia" as a possible adverse reaction. Experimentally, glibenclamide (moderately SUR1-selective) eliminated the beneficial effects of IPC, whereas mitiglinide (highly SUR1-selective) did not, suggesting that their different binding affinities may play a role.129 Another study showed that glimepiride did not block IPC, unlike glibenclamide,130 both of which are moderately SUR1 selective.128 This was attributable to the inability of glimepiride to block mitoKATP, whereas glibenclamide did, again illustrating the multiple pathways that underlie IPC.130 As reviewed elsewhere, concern over a possible link between sulfonylureas and adverse myocardial events extends back almost 40 years; however, recent clinical evidence seems more reassuring, but data are still mixed.131
KATP channel openers in theory could be beneficial in ischemic heart disease by inducing channel opening and thereby reducing Ca2+ influx, mimicking IPC. One drug in particular, diazoxide, is interesting because, in vitro, it is able to promote IPC; however, it is believed to have higher affinity for the mitochondrial than the sarcolemmal KATP channel. Despite this theoretical benefit, no KATP channel openers are regularly used clinically to treat disease. These channel openers are reviewed elsewhere.132
KATP Channels in the Endothelium
In the endothelium, KATP channels play an important role in the regulation of vascular tone. Vascular KATP channels are composed mainly of the SUR2B isoform and Kir6.2, although Kir6.1 may also associate with SUR2B in certain vascular tissue, including the coronary arteries.133 Vascular KATP channels are activated by vasodilators such as β-adrenergic agonists and adenosine via the protein kinase A pathway and are inhibited by vasoconstrictors such as angiotensin II via protein kinase C.134 Vasodilators produced during an ischemic insult are thought to diffuse from the myocardium and activate these channels. This results in hyperpolarization, reduced calcium flux, and vasodilation (Figure 3C).135
SUR Subunits Cause KATP Channel Dysfunction in Cardiac Disease
Evidence of a potential role for SUR in cardiovascular disease comes from muscle-specific SUR2 KO studies. SUR1 KO mice also have been generated, but these studies are beyond the scope of this discussion.136 A SUR2 KO was generated by deleting NBD1; therefore, this KO does not distinguish between SUR2A and SUR2B isoforms.137 SUR2 KO mice exhibited hypertension, sudden death, and increased coronary vasospasm.138 The presence of vasospasm and hypertension clearly implicates vascular smooth muscle KATP channels and the SUR2 isoform in the regulation of vascular tone. Interestingly, though, transgenic expression of normal SUR2B, which reconstitutes normal sarcolemmal KATP channels, does not abrogate the incidence of vasospasm in these SUR2-null mice, suggesting additional unknown effects of SUR2 on muscle cell biology.139 The pattern of ECG changes seen in these mice is the same as that observed in humans with Prinzmetal’s, or variant, angina,138 although no known human mutations in ABCC9 have yet been associated with spasm. However, a rare mutation found in an Italian population encoding for a Val734Ile mutation in ABCC9 has been associated with a 6.4-fold increased risk of early myocardial infarction (defined as myocardial infarction before 60 years of age) compared with control patients.140 At present, the pathophysiological mechanism behind this increased risk is not known, but given the excessive vasospasm noted in the SUR2 KO, the authors posit that this mutation may increase the incidence of vasospasm, resulting in myocardial infarction.
Another ABCC9 mutation in SUR2A has been identified recently in a patient with adrenergic-inducible atrial fibrillation.141 This mutation, T1547I, occurs at a highly conserved residue in the unique C-terminal 42-aa domain of SUR2A. As previously stated, this domain constitutes the only difference between SUR2A and SUR2B and is thought to play a major role in the differential gating exhibited by these 2 isoforms.113 This residue is predicted to be in close proximity to the Walker A motif of NBD2, and the T1547I mutation alters the normal hydrogen bonding that stabilizes this motif.141 This mutant SUR2A, coexpressed with Kir6.2, showed reduced responsiveness to ADP, while retaining the normal inhibitory effects of ATP, thus resulting in decreased channel gating.141
Experimental evidence also supports a possible role for SUR2A in ischemic heart disease. Using the rat-derived cardiac cell line, H9c2, exposure to 24 hours of mild hypoxia increased expression of SUR2A but not Kir6.2; this upregulation also led to a corresponding increase in plasma membrane KATP channel density.142 Of note, Kir6 is expressed at much higher levels than SUR2A in both adult cardiomyocytes143,144 and H9c2 cells.145 When cells pretreated with mild hypoxia (PO2 = 100 mm Hg), but not normoxia (PO2=140 mm Hg), were exposed to more severe hypoxia followed by reperfusion, they were protected against cell death.142 Transgenic mice overexpressing SUR2A show much improved cell survival and markedly reduced infarct size in response to ischemia, further supporting the role that increased SUR2A expression has on ischemic heart disease.144
In light of the data discussed above, it is interesting to note that there is no significant change in the structure of the myocardium of SUR2 KO mice despite the fact that these KO mice had no detectable myocardial SUR2 expression.123,137 Despite this, mutations in ABCC9 have been identified in idiopathic dilated cardiomyopathy patients.146 The 2 identified mutations disrupt the variable C terminus of SUR2A, again pointing to the importance of this structure in regulating KATP channels. These mutations both disrupt the tertiary structure of NBD2, specifically reducing the ATPase catalytic activity without affecting nucleotide binding. This reduced ATPase activity causes aberrant sensing of cellular energy status and prevents the normal regulation of channel activity by phosphotransfer systems such as CK.146 Because an estimated half of all cases of dilated cardiomyopathy are deemed to be idiopathic, it seems likely that further mutations affecting the ABCC9 gene will be found in the future.147,148
|
Conclusions |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
ABC proteins play critical roles in all organisms throughout nature. They regulate many processes critical to life. In the heart, the atypical ABC protein SUR plays a critical role in the regulation of KATP channels; this regulatory role is unique among ABC transporters described to date. SUR plays a key part in the intricate regulation between cellular energy status and membrane potential. Experimental models suggest that the cardiac and vascular isoform, SUR2, plays an important role in IPC and ischemic heart disease, coronary vasomotor tone, the development of hypertension, and heart failure. Despite this, much has yet to be learned about SUR and its role in cardiovascular disease. For instance, in SUR2 KO mice, coronary vasospasm is related to ST elevation and atrioventricular heart block on the ECG, yet the role of SUR in the cardiac electrical conduction system has yet to be elucidated to any significant extent.138 Furthermore, SUR2A levels have been shown to decline in an animal model of aging, but a role for SUR2A levels in human aging or an association between the development of cardiac disease and aging has yet to be established.149 Nonetheless, research on ABC proteins in the cardiovascular system will continue to progress, hopefully leading to future therapies targeted at cardiac disease.
|
Acknowledgments |
|---|
Sources of Funding
H.A. is supported by NIH grants K08 HL079387 and R01 HL087149, the Schweppe Foundation, the American Heart Association, and a grant from the American Cancer Society Illinois Chapter.
Disclosures
None.
|
Footnotes |
|---|
Original received October 4, 2007; revision received November 28, 2007; accepted December 17, 2007.
|
References |
|---|
|
TopAbstractIntroductionABC Proteins and Human...Structure of ABC ProteinsThe KATP Channel: Structure...The KATP Channel: Physiological...The KATP Channel: Physiological...ConclusionsReferences |
|---|
1. Dassa E. Phylogenetic and functional classification of ABC (ATP-binding cassette) systems. In Holland IB, Cole SPC, Kuchler K, Higgins CF, eds. ABC Proteins: From Bacteria to Man. San Diego: Academic Press; 2003: 3–35.
2. Dean M, Rzhetsky A, Allikmets R. Human and Drosophila ABC proteins. In Holland IB, Cole SPC, Kuchler K, Higgins CF, eds. ABC Proteins: From Bacteria to Man. San Diego: Academic Press; 2003: 47–61.
3. Linton KJ, Higgins CF. The Escherichia coli ATP-binding cassette (ABC) proteins. Mol Microbiol. 1998; 28: 5–13.[CrossRef][Medline] [Order article via Infotrieve]
4. Chang G. Multidrug resistance ABC transporters. FEBS Lett. 2003; 555: 102–105.[CrossRef][Medline] [Order article via Infotrieve]
5. Prasad R, Gaur NA, Gaur M, Komath SS. Efflux pumps in drug resistance of Candida. Infect Disord Drug Targets. 2006; 6: 69–83.[Medline] [Order article via Infotrieve]
6. Jungwirth H, Kuchler K. Yeast ABC transporters–a tale of sex, stress, drugs and aging. FEBS Lett. 2006; 580: 1131–1138.[CrossRef][Medline] [Order article via Infotrieve]
7. Geisler M, Murphy AS. The ABC of auxin transport: the role of p-glycoproteins in plant development. FEBS Lett. 2006; 580: 1094–1102.[CrossRef][Medline] [Order article via Infotrieve]
8. Klein M, Burla B, Martinoia E. The multidrug resistance-associated protein (MRP/ABCC) subfamily of ATP-binding cassette transporters in plants. FEBS Lett. 2006; 580: 1112–1122.[CrossRef][Medline] [Order article via Infotrieve]
9. Windsor B, Roux SJ, Lloyd A. Multiherbicide tolerance conferred by AtPgp1 and apyrase overexpression in Arabidopsis thaliana. Nat Biotechnol. 2003; 21: 428–433.[CrossRef][Medline] [Order article via Infotrieve]
10. Yazaki K. ABC transporters involved in the transport of plant secondary metabolites. FEBS Lett. 2006; 580: 1183–1191.[CrossRef][Medline] [Order article via Infotrieve]
11. Cavelier C, Lorenzi I, Rohrer L, von Eckardstein A. Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochim Biophys Acta. 2006; 1761: 655–666.[Medline] [Order article via Infotrieve]
12. Koch J, Tampe R. The macromolecular peptide-loading complex in MHC class I-dependent antigen presentation. Cell Mol Life Sci. 2006; 63: 653–662.[CrossRef][Medline] [Order article via Infotrieve]
13. Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005; 105: 1867–1874.
14. Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. 2006; 130: 908–925.[CrossRef][Medline] [Order article via Infotrieve]
15. Huai-Yun H, Secrest DT, Mark KS, Carney D, Brandquist C, Elmquist WF, Miller DW. Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells. Biochem Biophys Res Commun. 1998; 243: 816–820.[CrossRef][Medline] [Order article via Infotrieve]
16. Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992; 8: 67–113.[CrossRef][Medline] [Order article via Infotrieve]
17. Kubo Y, Sekiya S, Ohigashi M, Takenaka C, Tamura K, Nada S, Nishi T, Yamamoto A, Yamaguchi A. ABCA5 resides in lysosomes, and ABCA5 knockout mice develop lysosomal disease-like symptoms. Mol Cell Biol. 2005; 25: 4138–4149.
18. Ardehali H, Chen Z, Ko Y, Mejia-Alvarez R, Marban E. Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. Proc Natl Acad Sci U S A. 2004; 101: 11880–11885.
19. Ardehali H, O’Rourke B, Marban E. Cardioprotective role of the mitochondrial ATP-binding cassette protein 1. Circ Res. 2005; 97: 740–742.
20. Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, Wang J, Sosa-Pineda B, Murti KG, Schuetz JD. Identification of a mammalian mitochondrial porphyrin transporter. Nature. 2006; 443: 586–589.[Medline] [Order article via Infotrieve]
21. Kemp S, Wanders RJ. X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment. Mol Genet Metab. 2007; 90: 268–276.[CrossRef][Medline] [Order article via Infotrieve]
22. Dean M. The genetics of ATP-binding cassette transporters. Methods Enzymol. 2005; 400: 409–429.[Medline] [Order article via Infotrieve]
23. Hanrahan JW GM, Riordan JR. The cystic fibrosis transmembrane conductance regulator (ABCC7). In: In Holland IB, Cole SPC, Kuchler K, Higgins CF, eds. ABC Proteins: From Bacteria to Man. San Diego: Academic Press; 2003: 589–618.
24. Gadsby DC, Vergani P, Csanady L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 2006; 440: 477–483.[CrossRef][Medline] [Order article via Infotrieve]
25. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999; 22: 347–351.[CrossRef][Medline] [Order article via Infotrieve]
26. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J Jr, Hayden MR. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22: 336–345.[CrossRef][Medline] [Order article via Infotrieve]
27. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999; 22: 352–355.[CrossRef][Medline] [Order article via Infotrieve]
28. Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol. 2003; 23: 1322–1332.
29. Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998; 20: 233–238.[CrossRef][Medline] [Order article via Infotrieve]
30. Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch. 2007; 453: 643–659.[CrossRef][Medline] [Order article via Infotrieve]
31. Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993; 361: 726–730.[CrossRef][Medline] [Order article via Infotrieve]
32. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004; 350: 1296–1303.
33. Ban N, Matsumura Y, Sakai H, Takanezawa Y, Sasaki M, Arai H, Inagaki N. ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J Biol Chem. 2007; 282: 9628–9634.
34. Lefevre C, Audebert S, Jobard F, Bouadjar B, Lakhdar H, Boughdene-Stambouli O, Blanchet-Bardon C, Heilig R, Foglio M, Weissenbach J, Lathrop M, Prud’homme JF, Fischer J. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet. 2003; 12: 2369–2378.
35. de la Salle H, Zimmer J, Fricker D, Angenieux C, Cazenave JP, Okubo M, Maeda H, Plebani A, Tongio MM, Dormoy A, Hanau D. HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1. J Clin Invest. 1999; 103: R9–R13.[Medline] [Order article via Infotrieve]
36. Proks P, Shimomura K, Craig TJ, Girard CA, Ashcroft FM. Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Hum Mol Genet. 2007; 16: 2011–2019.
37. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet. 1999; 8: 743–749.
38. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, Bishop DF. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood. 2000; 96: 3256–3264.
39. Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F. The functions and structure of ABC transporters: implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr Drug Targets. 2006; 7: 893–909.[CrossRef][Medline] [Order article via Infotrieve]
40. Barnard JB, Richardson S, Sheldon S, Fildes J, Pravica V, Hutchinson IV, Leonard CT, Yonan N. The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection. Transplantation. 2006; 82: 1677–1682.[CrossRef][Medline] [Order article via Infotrieve]
41. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005; 20: 452–477.[CrossRef][Medline] [Order article via Infotrieve]
42. Meissner K, Heydrich B, Jedlitschky G, Meyer Zu Schwabedissen H, Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Bohm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK. The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart. J Histochem Cytochem. 2006; 54: 215–221.
43. Laguens RP, Lazarowski AJ, Cuniberti LA, Vera Janavel GL, Cabeza Meckert PM, Yannarelli GG, del Valle HF, Lascano EC, Negroni JA, Crottogini AJ. Expression of the MDR-1 gene-encoded P-glycoprotein in cardiomyocytes of conscious sheep undergoing acute myocardial ischemia followed by reperfusion. J Histochem Cytochem. 2007; 55: 191–197.
44. Lazarowski AJ, Garcia Rivello HJ, Vera Janavel GL, Cuniberti LA, Cabeza Meckert PM, Yannarelli GG, Mele A, Crottogini AJ, Laguens RP. Cardiomyocytes of chronically ischemic pig hearts express the MDR-1 gene-encoded P-glycoprotein. J Histochem Cytochem. 2005; 53: 845–850.
45. Jungsuwadee P, Cole MP, Sultana R, Joshi G, Tangpong J, Butterfield DA, St Clair DK, Vore M. Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice. Mol Cancer Ther. 2006; 5: 2851–2860.
46. Krause MS, Oliveira LP Jr, Silveira EM, Vianna DR, Rossato JS, Almeida BS, Rodrigues MF, Fernandes AJ, Costa JA, Curi R, de Bittencourt PI Jr. MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells? Cell Biochem Funct. 2007; 25: 23–32.[CrossRef][Medline] [Order article via Infotrieve]
47. Meng H, Vera I, Che N, Wang X, Wang SS, Ingram-Drake L, Schadt EE, Drake TA, Lusis AJ. Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics. Proc Natl Acad Sci U S A. 2007; 104: 4530–4535.
48. Oram JF, Vaughan AM. ATP-Binding cassette cholesterol transporters and cardiovascular disease. Circ Res. 2006; 99: 1031–1043.
49. Linton KJ. Structure and function of ABC transporters. Physiology (Bethesda). 2007; 22: 122–130.[CrossRef][Medline] [Order article via Infotrieve]
50. Schneider E, Hunke S. ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains. FEMS Microbiol Rev. 1998; 22: 1–20.[CrossRef][Medline] [Order article via Infotrieve]
51. Locher KP, Rees B, Koebnik R, Mitschler A, Moulinier L, Rosenbusch JP, Moras D. Transmembrane signaling across the ligand-gated FhuA receptor: crystal structures of free and ferrichrome-bound states reveal allosteric changes. Cell. 1998; 95: 771–778.[CrossRef][Medline] [Order article via Infotrieve]
52. Locher KP, Lee AT, Rees DC. The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science. 2002; 296: 1091–1098.
53. Pinkett HW, Lee AT, Lum P, Locher KP, Rees DC. An inward-facing conformation of a putative metal-chelate-type ABC transporter. Science. 2007; 315: 373–377.
54. Hollenstein K, Frei DC, Locher KP. Structure of an ABC transporter in complex with its binding protein. Nature. 2007; 446: 213–216.[CrossRef][Medline] [Order article via Infotrieve]
55. Higgins CF, Hiles ID, Salmond GP, Gill DR, Downie JA, Evans IJ, Holland IB, Gray L, Buckel SD, Bell AW, Hermodson MA. A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria. Nature. 1986; 323: 448–450.[CrossRef][Medline] [Order article via Infotrieve]
56. Hung LW, Wang IX, Nikaido K, Liu PQ, Ames GF, Kim SH. Crystal structure of the ATP-binding subunit of an ABC transporter. Nature. 1998; 396: 703–707.[CrossRef][Medline] [Order article via Infotrieve]
57. Karpowich N, Martsinkevich O, Millen L, Yuan YR, Dai PL, MacVey K, Thomas PJ, Hunt JF. Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. Structure. 2001; 9: 571–586.[Medline] [Order article via Infotrieve]
58. Biemans-Oldehinkel E, Doeven MK, Poolman B. ABC transporter architecture and regulatory roles of accessory domains. FEBS Lett. 2006; 580: 1023–1035.[CrossRef][Medline] [Order article via Infotrieve]
59. Hvorup RN, Goetz BA, Niederer M, Hollenstein K, Perozo E, Locher KP. Asymmetry in the structure of the ABC transporter-binding protein complex BtuCD-BtuF. Science. 2007; 317: 1387–1390.
60. Doolittle RF, Johnson MS, Husain I, Van Houten B, Thomas DC, Sancar A. Domainal evolution of a prokaryotic DNA repair protein and its relationship to active-transport proteins. Nature. 1986; 323: 451–453.[CrossRef][Medline] [Order article via Infotrieve]
61. Obmolova G, Ban C, Hsieh P, Yang W. Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature. 2000; 407: 703–710.[CrossRef][Medline] [Order article via Infotrieve]
62. Hopfner KP, Karcher A, Shin DS, Craig L, Arthur LM, Carney JP, Tainer JA. Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell. 2000; 101: 789–800.[CrossRef][Medline] [Order article via Infotrieve]
63. Hirano T. At the heart of the chromosome: SMC proteins in action. Nat Rev Mol Cell Biol. 2006; 7: 311–322.[CrossRef][Medline] [Order article via Infotrieve]
64. Kozak L, Gopal G, Yoon JH, Sauna ZE, Ambudkar SV, Thakurta AG, Dhar R. Elf1p, a member of the ABC class of ATPases, functions as a mRNA export factor in Schizosacchromyces pombe. J Biol Chem. 2002; 277: 33580–33589.
65. Andersen CB, Becker T, Blau M, Anand M, Halic M, Balar B, Mielke T, Boesen T, Pedersen JS, Spahn CM, Kinzy TG, Andersen GR, Beckmann R. Structure of eEF3 and the mechanism of transfer RNA release from the E-site. Nature. 2006; 443: 663–668.[CrossRef][Medline] [Order article via Infotrieve]
66. Bryan J, Aguilar-Bryan L. Sulfonylurea receptors: ABC transporters that regulate ATP-sensitive K(+) channels. Biochim Biophys Acta. 1999; 1461: 285–303.[Medline] [Order article via Infotrieve]
67. Matsuo M, Ueda K, Ryder T, Ashcroft F. The Sulfonylurea Receptor: an ABCC transporter that acts as an ion channel regulator. In Holland IB, Cole SPC, Kuchler K, Higgins CF, eds. ABC Proteins: From Bacteria to Man. San Diego: Academic Press; 2003: 551–575.
68. Inagaki N, Gonoi T, Clement JPt, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995; 270: 1166–1170.
69. Seino S. ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol. 1999; 61: 337–362.[CrossRef][Medline] [Order article via Infotrieve]
70. Chutkow WA, Simon MC, Le Beau MM, Burant CF. Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes. 1996; 45: 1439–1445.[Abstract]
71. Chutkow WA, Makielski JC, Nelson DJ, Burant CF, Fan Z. Alternative splicing of sur2 Exon 17 regulates nucleotide sensitivity of the ATP-sensitive potassium channel. J Biol Chem. 1999; 274: 13656–13665.
72. Shi NQ, Ye B, Makielski JC. Function and distribution of the SUR isoforms and splice variants. J Mol Cell Cardiol. 2005; 39: 51–60.[CrossRef][Medline] [Order article via Infotrieve]
73. Nichols CG. KATP channels as molecular sensors of cellular metabolism. Nature. 2006; 440: 470–476.[CrossRef][Medline] [Order article via Infotrieve]
74. Babenko AP, Bryan J. SUR-dependent modulation of KATP channels by an N-terminal KIR6.2 peptide. Defining intersubunit gating interactions. J Biol Chem. 2002; 277: 43997–44004.
75. Babenko AP, Bryan J. Sur domains that associate with and gate KATP pores define a novel gatekeeper. J Biol Chem. 2003; 278: 41577–41580.
76. Chan KW, Zhang H, Logothetis DE. N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J. 2003; 22: 3833–3843.[CrossRef][Medline] [Order article via Infotrieve]
77. Mikhailov MV, Campbell JD, de Wet H, Shimomura K, Zadek B, Collins RF, Sansom MS, Ford RC, Ashcroft FM. 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. EMBO J. 2005; 24: 4166–4175.[CrossRef][Medline] [Order article via Infotrieve]
78. Zerangue N, Schwappach B, Jan YN, Jan LY. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron. 1999; 22: 537–548.[CrossRef][Medline] [Order article via Infotrieve]
79. Sharma N, Crane A, Clement JPt, Gonzalez G, Babenko AP, Bryan J, Aguilar-Bryan L. The C terminus of SUR1 is required for trafficking of KATP channels. J Biol Chem. 1999; 274: 20628–20632.
80. Smith PC, Karpowich N, Millen L, Moody JE, Rosen J, Thomas PJ, Hunt JF. ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol Cell. 2002; 10: 139–149.[CrossRef][Medline] [Order article via Infotrieve]
81. Yamada M, Ishii M, Hibino H, Kurachi Y. Mutation in nucleotide-binding domains of sulfonylurea receptor 2 evokes Na-ATP-dependent activation of ATP-sensitive K+ channels: implication for dimerization of nucleotide-binding domains to induce channel opening. Mol Pharmacol. 2004; 66: 807–816.
82. Schwappach B, Zerangue N, Jan YN, Jan LY. Molecular basis for K(ATP) assembly: transmembrane interactions mediate association of a K+ channel with an ABC transporter. Neuron. 2000; 26: 155–167.[CrossRef][Medline] [Order article via Infotrieve]
83. Bryan J, Munoz A, Zhang X, Dufer M, Drews G, Krippeit-Drews P, Aguilar-Bryan L. ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflugers Arch. 2007; 453: 703–718.[CrossRef][Medline] [Order article via Infotrieve]
84. Hosy E, Derand R, Revilloud J, Vivaudou M. Remodelling of the SUR-Kir6.2 interface of the KATP channel upon ATP binding revealed by the conformational blocker rhodamine 123. J Physiol. 2007; 582: 27–39.
85. Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JPt, Boyd AE 3rd, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science. 1995; 268: 423–426.
86. Proks P, Lippiat JD. Membrane ion channels and diabetes. Curr Pharm Des. 2006; 12: 485–501.[CrossRef][Medline] [Order article via Infotrieve]
87. Gopel SO, Kanno T, Barg S, Weng XG, Gromada J, Rorsman P. Regulation of glucagon release in mouse -cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol. 2000; 528: 509–520.
88. Gopel SO, Kanno T, Barg S, Rorsman P. Patch-clamp characterisation of somatostatin-secreting -cells in intact mouse pancreatic islets. J Physiol. 2000; 528: 497–507.
89. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002; 51 (suppl 3): S368–S376.
90. Sun HS, Feng ZP, Miki T, Seino S, French RJ. Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. J Neurophysiol. 2006; 95: 2590–2601.
91. Nichols CG, Shyng SL, Nestorowicz A, Glaser B, Clement JPT, Gonzalez G, Aguilar-Bryan L, Permutt MA, Bryan J. Adenosine diphosphate as an intracellular regulator of insulin secretion. Science. 1996; 272: 1785–1787.[Abstract]
92. Cartier EA, Conti LR, Vandenberg CA, Shyng SL. Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci U S A. 2001; 98: 2882–2887.
93. Taschenberger G, Mougey A, Shen S, Lester LB, LaFranchi S, Shyng SL. Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels. J Biol Chem. 2002; 277: 17139–17146.
94. Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet. 2005; 14: 925–934.
95. Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP. Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes. 2000; 49: 1359–1366.[Abstract]
96. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006; 355: 456–466.
97. Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007; 56: 1930–1937.
98. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007; 316: 1341–1345.
99. Florez JC, Jablonski KA, Kahn SE, Franks PW, Dabelea D, Hamman RF, Knowler WC, Nathan DM, Altshuler D. Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program. Diabetes. 2007; 56: 531–536.
100. Zingman LV, Hodgson DM, Bienengraeber M, Karger AB, Kathmann EC, Alekseev AE, Terzic A. Tandem function of nucleotide binding domains confers competence to sulfonylurea receptor in gating ATP-sensitive K+ channels. J Biol Chem. 2002; 277: 14206–14210.
101. Flagg TP, Nichols CG. Sarcolemmal K(ATP) channels: what do we really know? J Mol Cell Cardiol. 2005; 39: 61–70.[CrossRef][Medline] [Order article via Infotrieve]
102. Masia R, Enkvetchakul D, Nichols CG. Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. J Mol Cell Cardiol. 2005; 39: 491–501.[CrossRef][Medline] [Order article via Infotrieve]
103. Matsuo M, Tanabe K, Kioka N, Amachi T, Ueda K. Different binding properties and affinities for ATP and ADP among sulfonylurea receptor subtypes, SUR1, SUR2A, and SUR2B. J Biol Chem. 2000; 275: 28757–28763.
104. Gribble FM, Tucker SJ, Ashcroft FM. The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. EMBO J. 1997; 16: 1145–1152.[CrossRef][Medline] [Order article via Infotrieve]
105. Zingman LV, Alekseev AE, Bienengraeber M, Hodgson D, Karger AB, Dzeja PP, Terzic A. Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance. Neuron. 2001; 31: 233–245.[CrossRef][Medline] [Order article via Infotrieve]
106. Dzeja PP, Terzic A. Phosphotransfer reactions in the regulation of ATP-sensitive K+ channels. FASEB J. 1998; 12: 523–529.
107. Carrasco AJ, Dzeja PP, Alekseev AE, Pucar D, Zingman LV, Abraham MR, Hodgson D, Bienengraeber M, Puceat M, Janssen E, Wieringa B, Terzic A. Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels. Proc Natl Acad Sci U S A. 2001; 98: 7623–7628.
108. Crawford RM, Budas GR, Jovanovic S, Ranki HJ, Wilson TJ, Davies AM, Jovanovic A. M-LDH serves as a sarcolemmal K(ATP) channel subunit essential for cell protection against ischemia. EMBO J. 2002; 21: 3936–3948.[CrossRef][Medline] [Order article via Infotrieve]
109. Abraham MR, Selivanov VA, Hodgson DM, Pucar D, Zingman LV, Wieringa B, Dzeja PP, Alekseev AE, Terzic A. Coupling of cell energetics with membrane metabolic sensing. Integrative signaling through creatine kinase phosphotransfer disrupted by M-CK gene knock-out. J Biol Chem. 2002; 277: 24427–24434.
110. Crawford RM, Ranki HJ, Botting CH, Budas GR, Jovanovic A. Creatine kinase is physically associated with the cardiac ATP-sensitive K+ channel in vivo. FASEB J. 2002; 16: 102–104.
111. Fang K, Csanady L, Chan KW. The N-terminal transmembrane domain (TMD0) and a cytosolic linker (L0) of sulphonylurea receptor define the unique intrinsic gating of KATP channels. J Physiol. 2006; 576: 379–389.
112. Reimann F, Gribble FM, Ashcroft FM. Differential response of K(ATP) channels containing SUR2A or SUR2B subunits to nucleotides and pinacidil. Mol Pharmacol. 2000; 58: 1318–1325.[Medline] [Order article via Infotrieve]
113. Yamada M, Kurachi Y. A functional role of the C-terminal 42 amino acids of SUR2A and SUR2B in the physiology and pharmacology of cardiovascular ATP-sensitive K(+) channels. J Mol Cell Cardiol. 2005; 39: 1–6.[CrossRef][Medline] [Order article via Infotrieve]
114. Matsuoka T, Matsushita K, Katayama Y, Fujita A, Inageda K, Tanemoto M, Inanobe A, Yamashita S, Matsuzawa Y, Kurachi Y. C-terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K(+) channels. Circ Res. 2000; 87: 873–880.
115. Matsushita K, Kinoshita K, Matsuoka T, Fujita A, Fujikado T, Tano Y, Nakamura H, Kurachi Y. Intramolecular interaction of SUR2 subtypes for intracellular ADP-Induced differential control of K(ATP) channels. Circ Res. 2002; 90: 554–561.
116. Lederer WJ, Nichols CG, Smith GL. The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition. J Physiol. 1989; 413: 329–349.
117. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124–1136.
118. Gumina RJ, Pucar D, Bast P, Hodgson DM, Kurtz CE, Dzeja PP, Miki T, Seino S, Terzic A. Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics. Am J Physiol Heart Circ Physiol. 2003; 284: H2106–H2113.
119. Kane GC, Behfar A, Dyer RB, O’Cochlain DF, Liu XK, Hodgson DM, Reyes S, Miki T, Seino S, Terzic A. KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension. Hum Mol Genet. 2006; 15: 2285–2297.
120. Zingman LV, Hodgson DM, Bast PH, Kane GC, Perez-Terzic C, Gumina RJ, Pucar D, Bienengraeber M, Dzeja PP, Miki T, Seino S, Alekseev AE, Terzic A. Kir6.2 is required for adaptation to stress. Proc Natl Acad Sci U S A. 2002; 99: 13278–13283.
121. Kane GC, Behfar A, Yamada S, Perez-Terzic C, O’Cochlain F, Reyes S, Dzeja PP, Miki T, Seino S, Terzic A. ATP-sensitive K+ channel knockout compromises the metabolic benefit of exercise training, resulting in cardiac deficits. Diabetes. 2004; 53 (suppl 3): S169–S175.
122. Yamada S, Kane GC, Behfar A, Liu XK, Dyer RB, Faustino RS, Miki T, Seino S, Terzic A. Protection conferred by myocardial ATP-sensitive K+ channels in pressure overload-induced congestive heart failure revealed in KCNJ11 Kir6.2-null mutant. J Physiol. 2006; 577: 1053–1065.
123. Stoller D, Kakkar R, Smelley M, Chalupsky K, Earley JU, Shi NQ, Makielski JC, McNally EM. Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress. J Mol Cell Cardiol. 2007; 43: 445–454.[CrossRef][Medline] [Order article via Infotrieve]
124. Bolli R. Preconditioning: a paradigm shift in the biology of myocardial ischemia. Am J Physiol Heart Circ Physiol. 2007; 292: H19–H27.
125. Sukhodub A, Jovanovic S, Du Q, Budas G, Clelland AK, Shen M, Sakamoto K, Tian R, Jovanovic A. AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol. 2007; 210: 224–236.[CrossRef][Medline] [Order article via Infotrieve]
126. Ardehali H, O’Rourke B. Mitochondrial K(ATP) channels in cell survival and death. J Mol Cell Cardiol. 2005; 39: 7–16.[CrossRef][Medline] [Order article via Infotrieve]
127. Zhou M, He HJ, Suzuki R, Liu KX, Tanaka O, Sekiguchi M, Itoh H, Kawahara K, Abe H. Localization of sulfonylurea receptor subunits, SUR2A and SUR2B, in rat heart. J Histochem Cytochem. 2007; 55: 795–804.
128. Quast U, Stephan D, Bieger S, Russ U. The impact of ATP-sensitive K+ channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium. Diabetes. 2004; 53 (suppl 3): S156–S164.
129. Ogawa K, Ikewaki K, Taniguchi I, Takatsuka H, Mori C, Sasaki H, Okazaki F, Shimizu M, Mochizuki S. Mitiglinide, a novel oral hypoglycemic agent, preserves the cardioprotective effect of ischemic preconditioning in isolated perfused rat hearts. Int Heart J. 2007; 48: 337–345.[CrossRef][Medline] [Order article via Infotrieve]
130. Mocanu MM, Maddock HL, Baxter GF, Lawrence CL, Standen NB, Yellon DM. Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. Circulation. 2001; 103: 3111–3116.
131. Thisted H, Johnsen SP, Rungby J. Sulfonylureas and the risk of myocardial infarction. Metabolism. 2006; 55: S16–S19.[CrossRef][Medline] [Order article via Infotrieve]
132. Jahangir A, Terzic A. K(ATP) channel therapeutics at the bedside. J Mol Cell Cardiol. 2005; 39: 99–112.[CrossRef][Medline] [Order article via Infotrieve]
133. Li L, Wu J, Jiang C. Differential expression of Kir6.1 and SUR2B mRNAs in the vasculature of various tissues in rats. J Membr Biol. 2003; 196: 61–69.[CrossRef][Medline] [Order article via Infotrieve]
134. Brayden JE. Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol. 2002; 29: 312–316.[CrossRef][Medline] [Order article via Infotrieve]
135. Opie L Channels, Pumps and Exchangers. Heart Physiology: From Cell to Circulation. Philadelphia: Lippincott, Williams & Wilkins; 2004: 73–118.
136. Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti-Berggren L, Gromada J, Berggren PO, Magnuson MA. Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem. 2002; 277: 37176–37183.
137. Chutkow WA, Samuel V, Hansen PA, Pu J, Valdivia CR, Makielski JC, Burant CF. Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proc Natl Acad Sci U S A. 2001; 98: 11760–11764.
138. Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF, McNally EM. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. J Clin Invest. 2002; 110: 203–208.[CrossRef][Medline] [Order article via Infotrieve]
139. Kakkar R, Ye B, Stoller DA, Smelley M, Shi NQ, Galles K, Hadhazy M, Makielski JC, McNally EM. Spontaneous coronary vasospasm in KATP mutant mice arises from a smooth muscle-extrinsic process. Circ Res. 2006; 98: 682–689.
140. Minoretti P, Falcone C, Aldeghi A, Olivieri V, Mori F, Emanuele E, Calcagnino M, Geroldi D. A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction. Clin Chim Acta. 2006; 370: 124–128.[CrossRef][Medline] [Order article via Infotrieve]
141. Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, Seino S, Asirvatham SJ, Jahangir A, Terzic A. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med. 2007; 4: 110–116.[CrossRef][Medline] [Order article via Infotrieve]
142. Crawford RM, Jovanovic S, Budas GR, Davies AM, Lad H, Wenger RH, Robertson KA, Roy DJ, Ranki HJ, Jovanovic A. Chronic mild hypoxia protects heart-derived H9c2 cells against acute hypoxia/reoxygenation by regulating expression of the SUR2A subunit of the ATP-sensitive K+ channel. J Biol Chem. 2003; 278: 31444–31455.
143. Ranki HJ, Budas GR, Crawford RM, Jovanovic A. Gender-specific difference in cardiac ATP-sensitive K(+) channels. J Am Coll Cardiol. 2001; 38: 906–915.
144. Du Q, Jovanovic S, Clelland A, Sukhodub A, Budas G, Phelan K, Murray-Tait V, Malone L, Jovanovic A. Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia. FASEB J. 2006; 20: 1131–1141.
145. Ranki HJ, Budas GR, Crawford RM, Davies AM, Jovanovic A. 17Beta-estradiol regulates expression of K(ATP) channels in heart-derived H9c2 cells. J Am Coll Cardiol. 2002; 40: 367–374.
146. Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O’Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet. 2004; 36: 382–387.[CrossRef][Medline] [Order article via Infotrieve]
147. Fatkin D, Graham RM. Molecular mechanisms of inherited cardiomyopathies. Physiol Rev. 2002; 82: 945–980.
148. Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N Engl J Med. 1994; 331: 1564–1575.
149. Ranki HJ, Crawford RM, Budas GR, Jovanovic A. Ageing is associated with a decrease in the number of sarcolemmal ATP-sensitive K+ channels in a gender-dependent manner. Mech Ageing Dev. 2002; 123: 695–705.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  P. H. Backx Sulfonylurea Receptor Expression Heterogeneity Suggests Chamber-Specific Roles for Sarcolemmal KATP Channels in Heart Circ. Res., December 5, 2008; 103(12): 1345 - 1347. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Farzaneh and A. Tinker Differences in the mechanism of metabolic regulation of ATP-sensitive K+ channels containing Kir6.1 and Kir6.2 subunits Cardiovasc Res, September 1, 2008; 79(4): 621 - 631. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||