doi: 10.1161/CIRCRESAHA.106.144501
© 2007 American Heart Association, Inc.
Reviews |
cAMP and cGMP Signaling Cross-Talk
Role of Phosphodiesterases and Implications for Cardiac Pathophysiology
From the Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine (M.Z.), Padova, Italy; and the Cardiology Section, Veterans Affairs Salt Lake City Health Care System (M.A.M.), and Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah.
Correspondence to Dr Manuela Zaccolo, Venetian Institute for Molecular Medicine, Room G210, Via Orus 2, Padova 35129, Italy. E-mail manuela.zaccolo{at}unipd.it
This Review is part of a thematic series on Phosphodiesterases, which includes the following articles:
Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases
Overview of PDEs and their Regulation
Regulation of Phosphodiesterase 3 (PDE3) and Inducible cAMP Early Repressor in the Heart
cAMP Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling
cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology
PDE5 and Regulation of Vessel and Heart Function
David A. Kass Editor
 |
Abstract |
|---|
 Top Abstract IntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
Cyclic nucleotide phosphodiesterases regulate cAMP-mediated signaling by controlling intracellular cAMP content. The cAMP-hydrolyzing activity of several families of cyclic nucleotide phosphodiesterases found in human heart is regulated by cGMP. In the case of PDE2, this regulation primarily involves the allosteric stimulation of cAMP hydrolysis by cGMP. For PDE3, cGMP acts as a competitive inhibitor of cAMP hydrolysis. Several cGMP-mediated responses in cardiac cells, including a potentiation of Ca2+ currents and a diminution of the responsiveness to ß-adrenergic receptor agonists, have been shown to result from the effects of cGMP on cAMP hydrolysis. These effects appear to be dependent on the specific spatial distribution of the cGMP-generating and cAMP-hydrolyzing proteins, as well as on the intracellular concentrations of the two cyclic nucleotides. Gaining a more precise understanding of how these cross-talk mechanisms are individually regulated and coordinated is an important direction for future research.
Key Words: phosphodiesterases • signaling cross-talk • cAMP • cGMP • compartmentalization
|
Introduction |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
The second messengers cAMP and cGMP are important regulators of cardiac function. cAMP, which is generated by adenylyl cyclases (AC) on G protein–coupled receptor stimulation by catecholamines, regulates the strength and frequency of cardiac contraction and relaxation. The main downstream effector of cAMP is protein kinase A (PKA),1 though cyclic nucleotide-gated ion channels and the exchange factor for Rap, Epac,2 are also cAMP targets. cGMP, which is generated by guanylyl cyclases (GC) in response to nitric oxide (NO) and natriuretic peptides, modulates inotropy and metabolic responses3 via the activation of its downstream effectors, protein kinase G (PKG) and cyclic nucleotide-gated channels. These two signaling pathways often exert opposing influences on cardiac function,3 in part as a consequence of the opposing effects of PKA- and PKG-mediated phosphorylation on target proteins.
A separate level of cross-talk between the cAMP and cGMP signaling pathways involves the activity of the cyclic nucleotide-degrading enzymes, phosphodiesterases (PDEs). In the heart, cGMP acts as a regulator of the activity of cAMP-hydrolyzing PDEs, such that the intracellular concentration of cGMP can influence the intracellular concentration of cAMP. The modulatory effects of cGMP on cAMP-hydrolyzing PDEs occur at nanomolar to micromolar concentrations of cGMP. This concentration range is comparable to that at which cGMP activates canonical targets such as PKG (Ka
100 nmol/L)4 and cyclic nucleotide-gated ion channels (Ka20 µmol/L).5 By virtue of this cross-talk mechanism, cAMP-hydrolyzing PDEs can serve as targets of cGMP-mediated signaling in the heart, and some of the effects of cGMP in cardiac myocytes may result from effects on the cAMP pathway.
Cardiac myocytes express several cGMP-regulated cAMP-hydrolyzing PDEs that differ with respect to subcellular localization, affinity, and specificity for cAMP and cGMP. As a consequence, cAMP and cGMP signaling pathways are connected in a complex network with a precise spatial organization. In this review, we focus on the mechanisms by which cGMP controls cAMP hydrolysis, and we examine how cGMP-regulated PDEs can impact cardiac function.
|
Cyclic Nucleotide-Mediated Signaling in the Heart Is Regulated by Cyclic Nucleotide-Hydrolyzing PDEs |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
The intracellular level of cyclic nucleotides reflects the balance of their synthesis and their degradation. Adenylyl cyclases, which synthesize cAMP, are a family of nine membrane-bound proteins that differ for their susceptibility to unique regulatory mechanisms.6 Of these, AC5 and AC6, both of which are Ca2+-inhibited, are expressed in the heart. cGMP is synthesized by two types of guanylyl cyclase, the soluble (sGC) and the particulate (pGC) forms. sGC is a ubiquitous cytosolic receptor that is activated by NO.7 pGCs comprise a family of 7 proteins, including the receptors for A- and B-type natriuretic peptides (ANP and BNP), and are localized to cell membranes.8
cAMP and cGMP are hydrolyzed exclusively by cyclic nucleotide PDEs, which therefore have a key role in regulating the signal conveyed by cAMP and cGMP. PDEs are encoded by at least 21 different genes that are grouped, based on sequence similarity, mode of regulation, and preference for cAMP or cGMP as substrate, into 11 gene families.9–11 Transcription from different initiation sites in these genes and differential splicing of their mRNAs results in the generation of >90 isoforms, many of which vary with respect to tissue distribution, intracellular localization, and cross-talk with other signaling cascades.
In cardiac myocytes, PDE activity determines the basal intracellular concentration of cAMP by continuously hydrolyzing the cAMP synthesized by constitutively active cyclases.12 PDEs also control the amplitude12 and duration12,13 of the cAMP response to external stimuli. Not all PDEs are equally engaged in modulating the cAMP signal.14 Instead, the functional coupling between individual G protein–coupled receptors and selected PDEs allows these PDEs to have specific roles in shaping the amplitude, duration, and location of the cAMP response to a given stimulus. Thus, isoforms of the PDE412,14,15 family were shown to have the greatest role in the control of cAMP generated by ß-adrenergic stimulation in neonatal cardiac myocytes, whereas PDE3 isoforms appeared to be involved in regulating cAMP content in a functionally distinct pool.12 Further dissection of the role of individual receptors in the spatial compartmentation of the cAMP signal came from a recent study on adult mouse myocytes, in which cAMP generated in response to ß1-adrenergic receptor agonists was shown to be hydrolyzed entirely by PDE4, whereas cAMP generated in response to ß2-adrenergic receptor agonists was hydrolyzed by multiple PDE isoforms.16 In another study, using selective ß1- or ß2-adrenergic receptor knockout mice, PDE4D was shown to be selectively involved in the control of cAMP diffusion from activated ß2-adrenergic receptors. Under normal conditions, cAMP generated in response to ß1-adrenergic receptors activates PKA and increases the rate of contraction, whereas cAMP generated in response to ß2-adrenergic receptor agonists does not. In ß1-adrenergic receptor knockout mice, however, inhibition of PDE4D allows the cAMP generated in response to ß2-adrenergic receptor agonists to activate PKA and increase the rate of contraction.17 Thus, in addition to controlling steady-state levels of cAMP and the temporal aspect of the cAMP signal, PDEs have a role in defining the spatial component of cAMP signaling.18,19 The function of individual PDEs in this aspect of signal transduction appears to be strictly dependent on their distribution within the three-dimensional matrix of the cell and on their location with respect to other regulatory and effector elements (see below).
In the heart, 7 PDE families have been described: PDE1,20 PDE2,20 PDE3,21 PDE4,22 PDE5,23 PDE8,24 and PDE925 (Figure 1). PDE1, PDE2, and PDE3 are dual-specificity enzymes that can hydrolyze both cAMP and cGMP; PDE4 and PDE8 selectively hydrolyze cAMP; and PDE5 and PDE9 selectively hydrolyze cGMP. Of the cAMP-hydrolyzing PDEs expressed in the heart, cGMP inhibits PDE3 and possibly PDE1, whereas PDE2 is activated by cGMP (Figure 2). These PDEs also differ with respect to their regulation through other signaling pathways (Figure 2). PDE1, for example, is unique among phosphodiesterases in being stimulated by Ca2+ and calmodulin. Furthermore, PKA-mediated phosphorylation of PDE1 reduces its affinity for Ca2+ and calmodulin, resulting in inhibition of its activity,26 whereas PKA-mediated phosphorylation enhances the catalytic activities of PDE327 and PDE4.28 In vitro, PDE5 activity has been shown to be increased both by PKA- and PKG-mediated phosphorylation.29 However, a role for PKA-mediated phosphorylation in vivo has not been firmly established, and, at least in smooth muscle cells, only PKG appears to be involved in PDE5 activation.30
|
|
It is clear that cyclic nucleotide signaling in heart cells is regulated by an array of different PDEs organized in a network of regulatory connections involving cAMP and cGMP, and that factors relating to the spatial organization and regulation of the network are of key importance in shaping the cyclic nucleotide response.
|
Spatial Control of Cyclic Nucleotide Signaling |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
The concept of compartmentalized cAMP signal transduction has been proposed to explain how the specificity of response necessary for appropriate functioning of the cell is attained.31 A particular focus has been placed on the localization of proteins of the cAMP signaling pathway to restricted intracellular domains.32 Such domains are organized by scaffolding proteins into complexes that may include receptors, effectors, modulators, and targets. This organization increases the probability of the molecular components of the pathway of interacting efficiently and selectively. PKA- ("A kinase")-anchoring proteins (AKAPs) have a key role in the compartmentation of cAMP/PKA signaling.32 AKAPs are multivalent scaffolding proteins that have been classified as a functional family based on their ability to anchor PKA via an amphipathic helix; more than 50 AKAPs have so far been identified. AKAPs tether PKA to specific intracellular locations in close proximity to specific modulators and targets, providing spatial regulation of PKA signaling events. Regulatory proteins, such as phosphatases (PP)33 and the PDEs34,35 themselves, are often included within such spatially confined signaling domains, providing a means to switch off the signal delivered by cAMP in specific locations. The notion that targeting of PDEs is important in cyclic nucleotide signaling came from work on PDE4s36,37; PDE4D3 has been shown to bind several AKAPs, including muscle-selective AKAP (mAKAP) in the heart.38
An example of how the cAMP signal is transduced through a multimeric signaling domain is the activation of the L-type Ca2+ channel on ß2-adrenergic receptor stimulation in hippocampal neurons. In these cells, a multiprotein assembly, comprising the ß2-adrenergic receptor, adenylyl cyclase, a heterotrimeric G protein, the AKAP MAP2B, PKA, the PKA-regulated Cav1.2 L-type Ca2+ channel, and the phosphatase PP2A, was identified.39 Activation of the ß2-adrenergic receptor was shown to lead to selective activation of the Cav1.2 channel, indicating that spatial confinement of the signaling molecules restricts signal propagation and results in local effector activation.39 Interestingly, a functional complex including a Ca2+-sensitive adenylyl cyclase, ß2-adrenergic receptor, PP2A, PKA, and Cav1.2 has recently been described in cardiac myocytes.40
An increasing body of evidence12,15,41–48 indicates that an additional mechanism that serves to maintain the compartmentalization of signaling events is one that allows the small, hydrophilic molecule cAMP to act as a "short-range" second messenger through limitation of its free diffusion.49 The hypothesis of the existence of separate pools of cAMP within cardiac myocytes was formulated more then 25 years ago on the basis of experimental data showing that the PKA recovered in particulate fractions of cardiac myocytes and the PKA recovered in soluble fractions were affected differently by the cAMP-raising hormone prostaglandin.50 The involvement of PDEs in this compartmentation had been suggested previously on the basis of biochemical studies.51,52 In the last decade, this hypothesis has received strong support thanks to the development of techniques that allow detection of cAMP in living cells. In experiments combining classical whole-cell patch clamp recordings of ICa and a double-barreled microperfusion system in frog ventricular myocytes, application of a ß2-adrenergic receptor agonist was shown to generate a localized increase of cAMP. In contrast, application of forskolin, a direct activator of AC, generated a more diffuse increase.42 It was only recently, though, that discrete microdomains with high cAMP content could be directly imaged in cardiac myocytes. By using a FRET-based real-time imaging approach that allows detection of cAMP with submicrometer spatial resolution,53 it was possible to directly visualize local pools of cAMP in cardiac myocytes in response to ß-adrenergic receptor stimulation.54 These microdomains of cAMP were completely abolished by the addition of PDE inhibitors,49 indicating a key role for these enzymes in determining the spatial information content of the cAMP signal.
Much less is known regarding the intracellular distribution and dynamics of cGMP. Some compartmentation of elements of the cGMP signaling pathway has been reported. Proteins such as myosin,55 the atrial natriuretic peptide receptor,56 and troponin T57, for example, seem to act as PKG-anchoring proteins. In addition, it has recently been reported that cGMP, like cAMP, shows restricted diffusion inside the cell, suggesting that spatial control may be as important for cGMP-mediated signaling as it is for cAMP-mediated signaling.58,59
|
cGMP-Stimulated cAMP Phosphodiesterases |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
Of the cAMP-hydrolyzing PDEs expressed in the heart, PDE2 is unique in being potently stimulated by cGMP. Three isoforms of PDE2—PDE2A1, PDE2A2 and PDE2A3—are generated from a single gene by alternative exon splicing.60 These 3 isoforms, some of which are expressed in the same cell,61 differ in their amino-terminal regions. The amino terminus of PDE2A2 is more hydrophobic than the amino termini of the PDE2A1 and PDE2A3 proteins (Figure 3). These differences in hydrophobicity may underlie the partitioning of PDE2A activity between the membrane-associated and soluble fractions of the cell.62 In cardiac myocytes, PDE2 has been found to be cytosolic as well as associated with the sarcolemma, the sarcoplasmic reticulum membrane,15,63 the Golgi apparatus,64 and the nuclear envelope.65 PDE2 hydrolyzes both cAMP and cGMP, with Km values of 30 µmol/L for cAMP and 10 µmol/L for cGMP.66 cGMP also binds to 1 of 2 regulatory GAF domains at the amino-terminus of PDE2, with a KD of approximately 0.3 µmol/L. This binding results in an allosteric modification of PDE2 that lowers the apparent Km for cAMP and results in activation of the cAMP-hydrolyzing activity of the enzyme.67,68 This allosteric stimulation of cAMP hydrolysis by cGMP is more important, quantitatively, than its competitive inhibition of cAMP hydrolysis, although cAMP hydrolysis can be inhibited in vitro by cGMP at high (>50 µmol/L) concentrations.69 Through such regulatory mechanisms, stimuli that elevate cGMP attenuate the cAMP signal.
|
Cross-talk between the cAMP and cGMP signaling pathways through PDE2 has important physiological functions. One example is the ANP-mediated control of blood pressure, in which stimulation of the glomerulosa cells in the adrenal cortex by ANP induces cGMP synthesis, leading to activation of PDE2 and a consequent decrease in intracellular cAMP concentration; this, in turn, is responsible for a reduction in aldosterone secretion.70 Cross-talk through PDE2 is also important in the heart. Activation of a cGMP-stimulated cAMP-hydrolyzing PDE is responsible for cholinergic attenuation of ß-adrenergic signaling in rabbit atrioventricular nodal cells.71 Similarly, in pacemaker cells, the effect of NO on heart rate is mediated, at least in part, by inhibition of L-type Ca2+ current (ICa) via a signaling pathway involving guanylyl cyclase activation, synthesis of cGMP and stimulation of a cGMP-stimulated PDE.72 In amphibian ventricular myocytes73 and human atrial myocytes, cGMP inhibits cAMP-enhanced ICa via activation of a cGMP-stimulated PDE.74 More recently, the activation of PDE2 by cGMP was shown to influence the cAMP response to ß-adrenergic stimulation in rat ventricular myocytes.15 In these cells, activation of soluble guanylyl cyclase by sodium nitroprusside leads to activation of PDE2 and a 50% reduction in the amplitude of the cAMP response to 10 µmol/L norepinephrine; this is accompanied by a profound reduction in the amplitude of intracellular Ca2+ transients and in the fractional shortening of the myocyte.
The contribution of PDE2 to the regulation of cAMP-mediated signaling is particularly selective. PDE2 is essentially ineffective in blocking the rise in intracellular cAMP levels in response to forskolin, which activates adenylyl cyclases nonselectively. In contrast, PDE2 blocks the rise in cAMP levels induced by ß-adrenergic receptor agonists.15 The mechanism by which norepinephrine recruits PDE2 for the hydrolysis of cAMP occurs, at least in part, via activation of ß3-adrenergic receptors and a consequent activation of endothelial nitric oxide synthase (eNOS). Activated eNOS generates NO, which stimulates cGMP synthesis by soluble guanylyl cyclase; this in turn activates the cAMP-hydrolyzing activity of PDE2.15 The selective effect of PDE2 on cAMP generated by ß-agonists suggests that PDE2 is tightly coupled to the ß-adrenergic receptor, so that PDE2 activity is highly compartmentalized to a limited pool of cAMP within the cell.
Such a mechanism, whereby catecholamines induce a rise of cAMP and simultaneously activate PDE2 to hydrolyze cAMP, may protect against excessive activation of the ß-adrenergic pathway in normal hearts, but may decrease contractile reserve in failing hearts, in which ß1- and ß2-adrenergic receptors are downregulated and cAMP/PKA signaling is blunted.75 cGMP-mediated activation of PDE2 and the resulting increase in cAMP hydrolysis may occur through two pathways. First, soluble guanylyl cyclase can be activated by NO generated by all 3 isoforms of NOS. These can be activated through a variety of mechanisms,76 including binding to calmodulin and phosphorylation by kinases such as PI3K/Akt,77 protein kinase C78, and PKA.76 In addition, cGMP is synthesized by particulate guanylyl cyclases, the receptors for natriuretic peptides. These mechanisms may contribute to the negative inotropic effects and attenuated responses to cAMP-raising agents that have been observed in association with increases in intracellular cGMP content.79–82 From this perspective, selective inhibition of PDE2 may be a potential new approach to the treatment of heart failure.
On the other hand, both NO83 and natriuretic peptides84 exert antihypertrophic effects on the heart85 that have been attributed, at least in part, to activation of cGMP-activated protein kinase (PKG) and its inhibitory effect on the L-type Ca2+ channel.86 Whether cGMP-mediated activation of PDE2 and consequent degradation of cAMP contribute to such antihypertrophic effects remains to be determined.
|
cGMP-Inhibited cAMP Phosphodiesterases |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
PDE3 cyclic nucleotide phosphodiesterases are perhaps the best characterized phosphodiesterases in human hearts, owing to the use of inhibitors of these enzymes as therapeutic agents in the treatment of heart failure for more than 2 decades. These enzymes bind with high affinity to both cAMP (Km
80 nmol/L) and cGMP (Km20 nmol/L), which are mutually competitive substrates. Because of their much higher catalytic rates (kcat’s) for cAMP than for cGMP, PDE3 phosphodiesterases appear to function principally as cGMP-inhibited cAMP-hydrolyzing enzymes.87 In human heart, 3 isoforms, which appear to be generated by alternative transcription and alternative translation from the PDE3A gene, have been identified.88–90 Their amino acid sequences are identical except for the presence of different lengths of N-terminal sequence, in which domains involved in intracellular localization and sites for activation by phosphorylation are found (Figure 4). PDE3A1 (originally identified as PDE3A-136) is a 136-kDa protein recovered exclusively in microsomal fractions of human myocardium. It contains 2 intracellular localizing domains, NHR1 and NHR2. NHR1 consists of hydrophobic loops that insert into intracellular membranes, whereas NHR2 appears to localize the enzyme through protein–protein interactions.91,92 PDE3A1 also contains a recently-confirmed site for phosphorylation and activation by PKB93 and sites for phosphorylation by PKA. PDE3A2 (formerly PDE3A-118), a 118-kDa protein recovered in both microsomal and cytosolic fractions, lacks NHR1 and probably lacks the PKB site, but retains NHR2 and the PKA sites. PDE3A3 (formerly PDE3A-94), a 94-kDa protein whose distribution is primarily cytosolic, lacks NHR1, NHR2, and the 3 phosphorylation sites. All 3 isoforms contain the C-terminal catalytic region, and are identical with respect to catalytic activity and sensitivity to cGMP and other inhibitors of cAMP hydrolysis.90 PDE3 isoforms account for most of cAMP-hydrolyzing activity in membrane-enriched fractions of human myocardium. Their contribution to cytosolic cAMP-hydrolyzing activity varies from >50% to <20% depending on the conditions under which activity is measured.90 In mouse hearts, PDE3B1, an isoform transcribed from the PDE3B gene, is expressed.21,94,95 Although the NHR1 sequence is longer in PDE3B1 than in PDE3A1, and the amino acid sequences of the 2 isoforms differ in the N erminus, their domain structures are similar.
|
A second family of cAMP phosphodiesterases whose cAMP-hydrolyzing activity might be inhibited by cGMP is PDE1. It should be emphasized, however, that while a role for cGMP in the regulation of cAMP signaling via PDE2 and PDE3 has been demonstrated both in vitro and in vivo, cGMP-mediated inhibition of the cAMP-hydrolyzing activity of PDE1 has been demonstrated only in vitro, and its relevance in vivo remains unestablished. PDE1 activity is represented abundantly in human heart.90,96 Whether this activity is relevant in human cardiac myocytes remains uncertain, as a study in rat ventricle identified PDE1 activity in whole myocardium but not in isolated myocytes.97 These phosphodiesterases, which are activated by Ca2+ and calmodulin, also hydrolyze cAMP and cGMP in a mutually competitive manner.26 Three PDE1 genes, PDE1A, PDE1B, and PDE1C, have been identified, with several splice variants.98,99 All 3 gene products exhibit a similar affinity for cGMP (Km=1 to 5 µmol/L), but differ in their affinity for cAMP: PDE1A has the lowest affinity (Km=50 to 100 µmol/L), PDE1B has an intermediate affinity (Km=7 to 24 µmol/L), and PDE1C has the highest affinity (Km<1 µmol/L).20 For all PDE1 isoforms, therefore, cAMP-hydrolyzing activity can be inhibited by cGMP; in the case of PDE1C, reciprocal and competitive inhibition between cAMP and cGMP has been reported in vitro.20,98 Recent studies indicate that PDE1 activity represents a relatively small amount of the cGMP-inhibited cAMP-hydrolyzing activity in membrane-enriched fractions of human myocardium, but may represent the major fraction of cGMP-inhibited cAMP-hydrolyzing activity in cytosolic fractions.90 Although the relative affinities and Vmax for cAMP and cGMP may support a possible role for PDE1 in cGMP-mediated cAMP hydrolysis, the access of PDE1 to cGMP pools in vivo is unclear. The lack of widely accessible specific inhibitors of PDE1 has been a limiting factor in experimental approaches, and the fact that the activity of these enzymes is highly dependent on intracellular Ca2+ concentrations adds to the complexity of this line of investigation, especially in cardiac myocytes.
Just as the expression of PDE2 provides a mechanism whereby stimuli that elevate cGMP can decrease cAMP-mediated signaling, the expression of PDE3 and, potentially, of PDE1 in human myocardium provides mechanisms through which stimuli that elevate cGMP can augment cAMP-mediated signaling.87 Several examples in which the regulation of the cAMP-hydrolyzing activity of PDE3 by cGMP has physiological consequences have been reported. In noncardiac cells, inhibition of the cAMP-hydrolyzing activity of PDE3 by cGMP contributes to the stimulation of renin secretion, the potentiation of vasodilatory responses to adrenomedullin, and the inhibition of TNF-
–induced NF-
B–dependent inflammatory responses in vascular smooth muscle cells.100–102 In cardiac sinoatrial cells, inhibition of cAMP hydrolysis by PDE3 appears to contribute to the potentiation of delayed rectifier K+ currents by cGMP.103 In frog ventricular myocytes, agents that raise intracellular cGMP content by stimulating soluble guanylyl cyclase potentiate L-type Ca2+ currents via inhibition of PDE3.104 A similar PDE3-dependent potentiation of L-type Ca2+ currents by cGMP-raising agents has been described in human atrial myocytes.105
|
Coordination of the Regulation of cAMP Metabolism by cGMP |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
The observations described above provide reasons to conclude that cGMP regulates cAMP-mediated signaling in cardiac myocytes by activating or inhibiting cAMP-hydrolyzing PDEs. An important question is whether the effects of cGMP on individual PDEs can be controlled independently. It seems to us there are at least 3 mechanisms through which this can occur. One has to do with the intracellular concentrations of cyclic nucleotides. The binding affinities of PDE1, PDE2, and PDE3 for cGMP vary by 2 orders of magnitude. Based on these differences, small elevations in cGMP levels might be predicted to cause selective inhibition of PDE3 isoforms; with intermediate cGMP levels, stimulation of PDE2 would also occur; and with higher cGMP levels, PDE1 activity could be potentially inhibited (Figure 5). Experimental evidence supports this mechanism. In human atrial myocytes cGMP was reported to regulate ICa by controlling the intracellular concentration of cAMP through opposing actions: intracellular perfusion with low concentrations of cGMP stimulated ICa, presumably by inhibiting PDE3, whereas perfusion with high concentrations of cGMP inhibited ICa, presumably by activating PDE2.73 A problem in determining whether different concentrations of cGMP can physiologically affect the activity of individual PDEs is that the actual concentrations of cGMP in the cell are unknown. Furthermore, in the case of competitive inhibitors, the action of cGMP would depend on the concurrent concentration of cAMP, and this, as has been noted, is highly compartment-specific.
|
This leads to consideration of a second mechanism, involving the roles of individual PDEs in regulating cAMP content. As noted earlier, the contribution of different PDEs to the regulation of cAMP metabolism is itself dependent on cAMP concentration, as well as on intracellular Ca2+ concentrations. One can imagine, therefore, that inhibition of PDE3 activity by cGMP may be more important at low concentrations of cAMP and Ca2+, whereas effects of cGMP on PDE2 and possibly on PDE1 may be more important under other conditions.90
A third mechanism has to do with the likelihood that the concentration of cGMP is not uniform within the cardiac myocyte at any one time. To the contrary, cGMP metabolism appears, like cAMP metabolism, to be regulated on a compartment-selective basis.58,59 Some of this selectivity has been demonstrated through experiments involving the coexpression in cardiac myocytes of pGC and sGC, which show distinct subcellular localization and are activated by different stimuli. In native tissue, an increase in cGMP signaling mediated through the stimulation of pGC by natriuretic peptides has been shown to have positive chronotropic and inotropic effects in cardiac myocytes.106–108 In contrast, stimulation of sGC by NO donors appears to have a negative inotropic effect in cardiac myocytes that is dependent on the phosphorylation of troponin I by PKG and the consequent decrease in myofilament Ca2+ sensitivity.80,81,109 In another study, performed in perfused rabbit atria, cGMP-mediated inhibition of PDE3 was shown to affect cAMP levels, atrial dynamics, and myocyte ANP release differently depending on whether cGMP was produced by pGC or sGC.110 Consistent with these studies, spatial confinement of cGMP was recently reported in rat adult ventricular myocytes. In these cells, stimulation of either sGC or pGC leads to the synthesis of cGMP in functionally independent pools having restricted access to individual cGMP-hydrolyzing PDEs. Thus, PDE2 and PDE5 appear to be engaged in degrading cGMP synthesized by sGC, whereas cGMP synthesized by pGC is hydrolyzed solely by PDE2.58 Based on this third mechanism, it is possible to predict the existence, within cardiac myocytes, of multiple independent signaling units through which distinct pools of cGMP can selectively affect specific cAMP-hydrolyzing PDEs and the associated pools of cAMP. This would lead, in turn, to changes in the phosphorylation of specific PKA substrates, with specific functional sequelae (Figure 6). PDE5 is likely to have a role in this process, and establishing which cGMP pool is controlled by PDE5 will be important. PDE5 has been shown to be localized to discrete compartments in cardiac myocytes111 and to have access only to a fraction of the cGMP produced in these cells,58 suggesting that it too has a spatially specific role.
|
All of the above considerations demonstrate the importance and the complexity of the mechanisms through which cGMP regulates cAMP hydrolysis in cardiac muscle. Much remains to be learned. One question relates to the possible contribution of effects on cAMP hydrolysis to other actions of cGMP in cardiac muscle. Hypertrophic responses to pressure overload and ß-adrenergic receptor stimulation in animal models are decreased when cGMP content is increased by PDE5 inhibition.86,112–117 PDE5 inhibition has been shown to reduce infarct size after coronary occlusion in animal models and to reduce necrosis and apoptosis in cultured cardiac myocytes subjected to hypoxia.118–120 Antiapoptotic effects of PDE5 inhibition have also been described in cardiac myocytes exposed to doxorubicin, together with a reduction in left ventricular dysfunction in animals treated with doxorubicin.121 Are effects of cGMP on cAMP hydrolysis involved in these actions?
Other questions relate to the signaling networks themselves. What is the topographical organization of the cGMP pools that are generated in response to different extracellular stimuli? What is the PDE composition of each signaling unit? What are the specific targets affected by each signaling unit? Are the individual units independent of each other? If not, to what extent are they interconnected? And, finally, are the answers to these questions different in normal and diseased myocardium? Future work focused on these issues will further our understanding of the architecture of the cAMP/cGMP signaling network, and may lead to new insights into the pathophysiology of heart disease and new strategies for its treatment.
|
Acknowledgments |
|---|
We thank Dr Marco Berrera for helping with some of the figures.
Sources of Funding
This work was supported by grants from Telethon Italy (TCP00089 and GGP05113), the Italian Cystic Fibrosis Research Foundation, the Fondazione Compagnia di San Paolo, the HFSPO (RGP0001/2005-C), and the EC (LSHB-CT-2006-037189) to M.Z.; a Merit Review Award from the United States Department of Veterans Affairs to M.A.M.; and a grant from the Fondation Leducq (O6 CVD 02) to M.Z. and M.A.M.
Disclosures
None.
|
Footnotes |
|---|
Original received November 11, 2006; revision received March 20, 2007; accepted March 27, 2007.
|
References |
|---|
|
TopAbstractIntroductionCyclic Nucleotide-Mediated...Spatial Control of Cyclic...cGMP-Stimulated cAMP...cGMP-Inhibited cAMP...Coordination of the Regulation...References |
|---|
1. Schaub MC, Hefti MA, Zaugg M. Integration of calcium with the signaling network in cardiac myocytes. J Mol Cell Cardiol. 2006; 41: 183–214.[CrossRef][Medline] [Order article via Infotrieve]
2. Bos JL. Epac proteins: Multi-purpose camp targets. Trends Biochem Sci. 2006; 31: 680–686.[CrossRef][Medline] [Order article via Infotrieve]
3. Shah AM, MacCarthy PA. Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther. 2000; 86: 49–86.[CrossRef][Medline] [Order article via Infotrieve]
4. Ruth P, Landgraf W, Keilbach A, May B, Egleme C, Hofmann F. The activation of expressed cGMP-dependent protein kinase isozymes i alpha and i beta is determined by the different amino-termini. Eur J Biochem. 1991; 202: 1339–1344.[Medline] [Order article via Infotrieve]
5. Biel M, Zong X, Distler M, Bosse E, Klugbauer N, Murakami M, Flockerzi V, Hofmann F. Another member of the cyclic nucleotide-gated channel family, expressed in testis, kidney, and heart. Proc Natl Acad Sci U S A. 1994; 91: 3505–3509.
6. Cooper DM. Regulation and organization of adenylyl cyclases and camp. Biochem J. 2003; 375: 517–529.[CrossRef][Medline] [Order article via Infotrieve]
7. Kuhn M. Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-A. Circ Res. 2003; 93: 700–709.
8. Padayatti PS, Pattanaik P, Ma X, van den Akker F. Structural insights into the regulation and the activation mechanism of mammalian guanylyl cyclases. Pharmacol Ther. 2004; 104: 83–99.[CrossRef][Medline] [Order article via Infotrieve]
9. Francis SH, Turko IV, Corbin JD. Cyclic nucleotide phosphodiesterases: Relating structure and function. Prog Nucleic Acid Res Mol Biol. 2001; 65: 1–52.[Medline] [Order article via Infotrieve]
10. Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents. Pharmacol Ther. 2006; 109: 366–398.[CrossRef][Medline] [Order article via Infotrieve]
11. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacol Rev. 2006; 58: 488–520.
12. Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M. Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res. 2004; 95: 67–75.
13. Terrin A, Di Benedetto G, Pertegato V, Cheung YF, Baillie G, Elvassore N, Prinz A, Herberg FW, Houslay MD, Zaccolo M. PGE1 stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: Role of compartmentalized phosphodiesterases. The Journal of Cell Biology. 2006.
14. Rochais F, Abi-Gerges A, Horner K, Lefebvre F, Cooper DM, Conti M, Fischmeister R, Vandecasteele G. A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ Res. 2006; 98: 1081–1088.
15. Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung YF, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M. Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res. 2006; 98: 226–234.
16. Nikolaev VO, Bunemann M, Schmitteckert E, Lohse MJ, Engelhardt S. Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching beta1-adrenergic but locally confined beta2-adrenergic receptor-mediated signaling. Circ Res. 2006; 99: 1084–1091.
17. Xiang Y, Naro F, Zoudilova M, Jin SL, Conti M, Kobilka B. Phosphodiesterase 4D is required for beta2 adrenoceptor subtype-specific signaling in cardiac myocytes. Proc Natl Acad Sci U S A. 2005; 102: 909–914.
18. Zaccolo M, Magalhaes P, Pozzan T. Compartmentalisation of cAMP and Ca(2+) signals. Curr Opin Cell Biol. 2002; 14: 160–166.[CrossRef][Medline] [Order article via Infotrieve]
19. Houslay MD, (2006). A rsk(y) relationship with promiscuous PKA. Sci STKE. 2006; pe32.
20. Loughney K, Martins TJ, Harris EA, Sadhu K, Hicks JB, Sonnenburg WK, Beavo JA, Ferguson K. Isolation and characterization of cDNAS corresponding to two human calcium, calmodulin-regulated, 3',5'-cyclic nucleotide phosphodiesterases. J Biol Chem. 1996; 271: 796–806.
21. Meacci E, Taira M, Moos M, Jr., Smith CJ, Movsesian MA, Degerman E, Belfrage P, Manganiello V. Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase. Proc Natl Acad Sci U S A. 1992; 89: 3721–3725.
22. Kostic MM, Erdogan S, Rena G, Borchert G, Hoch B, Bartel S, Scotland G, Huston E, Houslay MD, Krause EG. Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxo-prostacyclin-preconditioned rat heart. J Mol Cell Cardiol. 1997; 29: 3135–3146.[CrossRef][Medline] [Order article via Infotrieve]
23. Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM, Kass DA. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. Faseb J. 2001; 15: 1718–1726.
24. Soderling SH, Bayuga SJ, Beavo JA. Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase. Proc Natl Acad Sci U S A. 1998; 95: 8991–8996.
25. Onody A, Zvara A, Hackler L, Jr., Vigh L, Ferdinandy P, Puskas LG. Effect of classic preconditioning on the gene expression pattern of rat hearts: A DNA microarray study. FEBS Lett. 2003; 536: 35–40.[CrossRef][Medline] [Order article via Infotrieve]
26. Sharma RK, Hickie RA. Phosphodiesterases inhibitors. San Diego: Academic Press; 1996.
27. Manganiello VC, Degerman E. Cyclic nucleotide phosphodiesterases (PDEs): Diverse regulators of cyclic nucleotide signals and inviting molecular targets for novel therapeutic agents. Thromb Haemost. 1999; 82: 407–411.[Medline] [Order article via Infotrieve]
28. Oki N, Takahashi SI, Hidaka H, Conti M. Short term feedback regulation of cAMP in FRTl-5 thyroid cells. Role of PDE4D3 phosphodiesterase activation. J Biol Chem. 2000; 275: 10831–10837.
29. Turko IV, Francis SH, Corbin JD. Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. Biochem J. 1998; 329 (Pt 3): 505–510.[Medline] [Order article via Infotrieve]
30. Rybalkin SD, Rybalkina IG, Feil R, Hofmann F, Beavo JA. Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem. 2002; 277: 3310–3317.
31. Brunton LL, Hayes JS, Mayer SE. Functional compartmentation of cyclic AMP and protein kinase in heart. Adv Cyclic Nucleotide Res. 1981; 14: 391–397.[Medline] [Order article via Infotrieve]
32. Wong W, Scott JD. Akap signalling complexes: Focal points in space and time. Nat Rev Mol Cell Biol. 2004; 5: 959–970.[CrossRef][Medline] [Order article via Infotrieve]
33. Chen L, Kurokawa J, Kass RS. Phosphorylation of the A-kinase-anchoring protein yotiao contributes to protein kinase a regulation of a heart potassium channel. J Biol Chem. 2005; 280: 31347–31352.
34. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: Modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003; 370: 1–18.[CrossRef][Medline] [Order article via Infotrieve]
35. Baillie GS, Scott JD, Houslay MD. Compartmentalisation of phosphodiesterases and protein kinase A: Opposites attract. FEBS Lett. 2005; 579: 3264–3270.[CrossRef][Medline] [Order article via Infotrieve]
36. Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M. Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. J Biol Chem. 2001; 276: 11189–11198.
37. Beard MB, Huston E, Campbell L, Gall I, McPhee I, Yarwood S, Scotland G, Houslay MD. In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting. Cell Signal. 2002; 14: 453–465.[CrossRef][Medline] [Order article via Infotrieve]
38. Dodge KL, Khouangsathiene S, Kapiloff MS, Mouton R, Hill EV, Houslay MD, Langeberg LK, Scott JD. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module. Embo J. 2001; 20: 1921–1930.[CrossRef][Medline] [Order article via Infotrieve]
39. Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW. A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel cav1.2. Science. 2001; 293: 98–101.
40. Balijepalli RC, Foell JD, Hall DD, Hell JW, Kamp TJ. Localization of cardiac l-type Ca(2+) channels to a caveolar macromolecular signaling complex is required for beta(2)-adrenergic regulation. Proc Natl Acad Sci U S A. 2006; 103: 7500–7505.
41. Barnes AP, Livera G, Huang P, Sun C, O’Neal WK, Conti M, Stutts MJ, Milgram SL. Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium. J Biol Chem. 2005; 280: 7997–8003.
42. Jurevicius J, Fischmeister R. cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. Proc Natl Acad Sci U S A. 1996; 93: 295–299.
43. Rich TC, Tse TE, Rohan JG, Schaack J, Karpen JW. In vivo assessment of local phosphodiesterase activity using tailored cyclic nucleotide-gated channels as cAMP sensors. J Gen Physiol. 2001; 118: 63–78.
44. Dodge-Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, Kapiloff MS, Scott JD. The protein kinase A anchoring protein makap coordinates two integrated cAMP effector pathways. Nature. 2005; 437: 574–578.[CrossRef][Medline] [Order article via Infotrieve]
45. DiPilato LM, Cheng X, Zhang J. Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signalling within discrete subcellular compartments. Proc Natl Acad Sci. 2004; 101: 16513–16518.
46. Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin SL, Conti M, Marks AR. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell. 2005; 123: 25–35.[CrossRef][Medline] [Order article via Infotrieve]
47. Zhang J, Hupfeld CJ, Taylor SS, Olefsky JM, Tsien RY. Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes. Nature. 2005; 437: 569–573.[CrossRef][Medline] [Order article via Infotrieve]
48. Sayner SL, Alexeyev M, Dessauer CW, Stevens T. Soluble adenylyl cyclase reveals the significance of cAMP compartmentation on pulmonary microvascular endothelial cell barrier. Circ Res. 2006; 98: 675–681.
49. Zaccolo M, Di Benedetto G, Lissandron V, Mancuso L, Terrin A, Zamparo I. Restricted diffusion of a freely diffusible second messenger: Mechanisms underlying compartmentalized cAMP signalling. Biochem Soc Trans. 2006; 34: 495–497.[CrossRef][Medline] [Order article via Infotrieve]
50. Buxton IL, Brunton LL. Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes. J Biol Chem. 1983; 258: 10233–10239.
51. Rapundalo ST, Solaro RJ, Kranias EG. Inotropic responses to isoproterenol and phosphodiesterase inhibitors in intact guinea pig hearts: Comparison of cyclic AMP levels and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins. Circ Res. 1989; 64: 104–111.
52. Hohl CM, Li QA. Compartmentation of cAMP in adult canine ventricular myocytes. Relation to single-cell free Ca2+ transients. Circ Res. 1991; 69: 1369–1379.
53. Zaccolo M, Pozzan T. Imaging signal transduction in living cells with GFP-based probes. IUBMB Life. 2000; 49: 375–379.[Medline] [Order article via Infotrieve]
54. Zaccolo M, Pozzan T. Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science. 2002; 295: 1711–1715.
55. Vo NK, Gettemy JM, Coghlan VM. Identification of cGMP-dependent protein kinase anchoring proteins (gkaps). Biochem Biophys Res Commun. 1998; 246: 831–835.[CrossRef][Medline] [Order article via Infotrieve]
56. Airhart N, Yang YF, Roberts CT, Jr., Silberbach M. Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction. J Biol Chem. 2003; 278: 38693–38698.
57. Yuasa K, Michibata H, Omori K, Yanaka N. A novel interaction of cGMP-dependent protein kinase i with troponin t. J Biol Chem. 1999; 274: 37429–37434.
58. Castro LR, Verde I, Cooper DM, Fischmeister R. Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation. 2006; 113: 2221–2228.
59. Piggott LA, Hassell KA, Berkova Z, Morris AP, Silberbach M, Rich TC. Natriuretic peptides and nitric oxide stimulate cGMP synthesis in different cellular compartments. J Gen Physiol. 2006; 128: 3–14.
60. Rosman GJ, Martins TJ, Sonnenburg WK, Beavo JA, Ferguson K, Loughney K. Isolation and characterization of human cDNAS encoding a cGMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase. Gene. 1997; 191: 89–95.[CrossRef][Medline] [Order article via Infotrieve]
61. Epstein PM, Paskind M, Yang Q, Cong H, Chen JC, Li J, Reenan R. Co-expression of three spice variants of cGMP-stimulated phosphodiesterase (PDE2). Naunyn Schmiedeber’s Arch Pharmacol. 1998; 538.
62. Yang Q, Paskind M, Bolger G, Thompson WJ, Repaske DR, Cutler LS, Epstein PM. A novel cyclic GMP stimulated phosphodiesterase from rat brain. Biochem Biophys Res Commun. 1994; 205: 1850–1858.[CrossRef][Medline] [Order article via Infotrieve]
63. Lugnier C, Komas N. Modulation of vascular cyclic nucleotide phosphodiesterases by cyclic GMP: Role in vasodilatation. Eur Heart J. 1993; 14 Suppl I: 141–148.
64. Geoffroy V, Fouque F, Nivet V, Clot JP, Lugnier C, Desbuquois B, Benelli C. Activation of a cGMP-stimulated cAMP phosphodiesterase by protein kinase C in a liver Golgi-endosomal fraction. Eur J Biochem. 1999; 259: 892–900.[Medline] [Order article via Infotrieve]
65. Lugnier C, Keravis T, Le Bec A, Pauvert O, Proteau S, Rousseau E. Characterization of cyclic nucleotide phosphodiesterase isoforms associated to isolated cardiac nuclei. Biochim Biophys Acta. 1999; 1472: 431–446.[Medline] [Order article via Infotrieve]
66. Martins TJ, Mumby MC, Beavo JA. Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J Biol Chem. 1982; 257: 1973–1979.
67. Martinez SE, Beavo JA, Hol WG. Gaf domains: Two-billion-year-old molecular switches that bind cyclic nucleotides. Mol Intervent. 2002; 2: 317–323.
68. Michie AM, Lobban M, Muller T, Harnett MM, Houslay MD. Rapid regulation of PDE-2 and PDE-4 cyclic amp phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: Analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (ehna) and rolipram. Cell Signal. 1996; 8: 97–110.[CrossRef][Medline] [Order article via Infotrieve]
69. Beavo JA, Hardman JG, Sutherland EW. Stimulation of adenosine 3',5'-monophosphate hydrolysis by guanosine 3',5'-monophosphate. J Biol Chem. 1971; 246: 3841–3846.
70. MacFarland RT, Zelus BD, Beavo JA. High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. J Biol Chem. 1991; 266: 136–142.
71. Han X, Kobzik L, Balligand JL, Kelly RA, Smith TW. Nitric oxide synthase (NOS3)-mediated cholinergic modulation of Ca2+ current in adult rabbit atrioventricular nodal cells. Circ Res. 1996; 78: 998–1008.
72. Han X, Shimoni Y, Giles WR. A cellular mechanism for nitric oxide-mediated cholinergic control of mammalian heart rate. J Gen Physiol. 1995; 106: 45–65.
73. Mery PF, Pavoine C, Belhassen L, Pecker F, Fischmeister R. Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. J Biol Chem. 1993; 268: 26286–26295.
74. Rivet-Bastide M, Vandecasteele G, Hatem S, Verde I, Benardeau A, Mercadier JJ, Fischmeister R. cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. J Clin Invest. 1997; 99: 2710–2718.[Medline] [Order article via Infotrieve]
75. Brodde OE. Beta-adrenoceptors in cardiac disease. Pharmacol Ther. 1993; 60: 405–430.[CrossRef][Medline] [Order article via Infotrieve]
76. Sessa WC. eNOS at a glance. J Cell Sci. 2004; 117: 2427–2429.
77. Dimmeler S, Assmus B, Hermann C, Haendeler J, Zeiher AM. Fluid shear stress stimulates phosphorylation of AKT in human endothelial cells: Involvement in suppression of apoptosis. Circ Res. 1998; 83: 334–341.
78. Partovian C, Zhuang Z, Moodie K, Lin M, Ouchi N, Sessa WC, Walsh K, Simons M. PKCalpha activates eNOS and increases arterial blood flow in vivo. Circ Res. 2005; 97: 482–487.
79. Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci U S A. 1993; 90: 347–351.
80. Vila-Petroff MG, Younes A, Egan J, Lakatta EG, Sollott SJ. Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res. 1999; 84: 1020–1031.
81. Wegener JW, Nawrath H, Wolfsgruber W, Kuhbandner S, Werner C, Hofmann F, Feil R. cGMP-dependent protein kinase I mediates the negative inotropic effect of cGMP in the murine myocardium. Circ Res. 2002; 90: 18–20.
82. Pierkes M, Gambaryan S, Boknik P, Lohmann SM, Schmitz W, Potthast R, Holtwick R, Kuhn M. Increased effects of c-type natriuretic peptide on cardiac ventricular contractility and relaxation in guanylyl cyclase A-deficient mice. Cardiovasc Res. 2002; 53: 852–861.
83. Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O’Rourke B, Rodriguez ER, Huang PL, Lima JA, Berkowitz DE, Hare JM. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature. 2002; 416: 337–339.[Medline] [Order article via Infotrieve]
84. Rosenkranz AC, Woods RL, Dusting GJ, Ritchie RH. Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: Importance of cyclic GMP. Cardiovasc Res. 2003; 57: 515–522.
85. Booz GW. Putting the brakes on cardiac hypertrophy: Exploiting the no-cGMP counter-regulatory system. Hypertension. 2005; 45: 341–346.
86. Fiedler B, Lohmann SM, Smolenski A, Linnemuller S, Pieske B, Schroder F, Molkentin JD, Drexler H, Wollert KC. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci U S A. 2002; 99: 11363–11368.
87. Shakur Y, Holst LS, Landstrom TR, Movsesian M, Degerman E, Manganiello V. Regulation and function of the cyclic nucleotide phosphodiesterase (PDE3) gene family. Prog Nucleic Acid Res Mol Biol. 2001; 66: 241–277.[Medline] [Order article via Infotrieve]
88. Choi YH, Ekholm D, Krall J, Ahmad F, Degerman E, Manganiello VC, Movsesian MA. Identification of a novel isoform of the cyclic-nucleotide phosphodiesterase PDE3A expressed in vascular smooth-muscle myocytes. Biochem J. 2001; 353: 41–50.[Medline] [Order article via Infotrieve]
89. Wechsler J, Choi YH, Krall J, Ahmad F, Manganiello VC, Movsesian MA. Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes. J Biol Chem. 2002; 277: 38072–38078.
90. Hambleton R, Krall J, Tikishvili E, Honeggar M, Ahmad F, Manganiello VC, Movsesian MA. Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. J Biol Chem. 2005; 280: 39168–39174.
91. Kenan Y, Murata T, Shakur Y, Degerman E, Manganiello VC. Functions of the n-terminal region of cyclic nucleotide phosphodiesterase 3 (PDE 3) isoforms. J Biol Chem. 2000; 275: 12331–12338.
92. Shakur Y, Takeda K, Kenan Y, Yu ZX, Rena G, Brandt D, Houslay MD, Degerman E, Ferrans VJ, Manganiello VC. Membrane localization of cyclic nucleotide phosphodiesterase 3 (PDE3). Two N-terminal domains are required for the efficient targeting to, and association of, PDE3 with endoplasmic reticulum. J Biol Chem. 2000; 275: 38749–38761.
93. Han SJ, Vaccari S, Nedachi T, Andersen CB, Kovacina KS, Roth RA, Conti M. Protein kinase B/AKT phosphorylation of PDE3A and its role in mammalian oocyte maturation. Embo J. 2006; 25: 5716–5725.[CrossRef][Medline] [Order article via Infotrieve]
94. Taira M, Hockman SC, Calvo JC, Belfrage P, Manganiello VC. Molecular cloning of the rat adipocyte hormone-sensitive cyclic GMP-inhibited cyclic nucleotide phosphodiesterase. J Biol Chem. 1993; 268: 18573–18579.
95. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell. 2004; 118: 375–387.[CrossRef][Medline] [Order article via Infotrieve]
96. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol. 1999; 83: 3C–12C.[Medline] [Order article via Infotrieve]
97. Bode DC, Kanter JR, Brunton LL. Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue. Circ Res. 1991; 68: 1070–1079.
98. Yan C, Zhao AZ, Bentley JK, Beavo JA. The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem. 1996; 271: 25699–25706.
99. Kakkar R, Raju RV, Sharma RK. Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1). Cell Mol Life Sci. 1999; 55: 1164–1186.[CrossRef][Medline] [Order article via Infotrieve]
100. Kurtz A, Gotz KH, Hamann M, Kieninger M, Wagner C. Stimulation of renin secretion by NO donors is related to the cAMP pathway. Am J Physiol. 1998; 274: F709–F717.[Medline] [Order article via Infotrieve]
101. Aizawa T, Wei H, Miano JM, Abe J, Berk BC, Yan C. Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res. 2003; 93: 406–413.
102. Fung E, Fiscus RR. Adrenomedullin induces direct (endothelium-independent) vasorelaxations and cyclic adenosine monophosphate elevations that are synergistically enhanced by brain natriuretic peptide in isolated rings of rat thoracic aorta. J Cardiovasc Pharmacol. 2003; 41: 849–855.[CrossRef][Medline] [Order article via Infotrieve]
103. Shimizu K, Shintani Y, Ding WG, Matsuura H, Bamba T. Potentiation of slow component of delayed rectifier K(+) current by cGMP via two distinct mechanisms: Inhibition of phosphodiesterase 3 and activation of protein kinase G. Br J Pharmacol. 2002; 137: 127–137.[CrossRef][Medline] [Order article via Infotrieve]
104. Frace AM, Mery PF, Fischmeister R, Hartzell HC. Rate-limiting steps in the beta-adrenergic stimulation of cardiac calcium current. J Gen Physiol. 1993; 101: 337–353.
105. Vandecasteele G, Verde I, Rucker-Martin C, Donzeau-Gouge P, Fischmeister R. Cyclic GMP regulation of the l-type Ca(2+) channel current in human atrial myocytes. J Physiol. 2001; 533: 329–340.
106. Beaulieu P, Cardinal R, Page P, Francoeur F, Tremblay J, Lambert C. Positive chronotropic and inotropic effects of C-type natriuretic peptide in dogs. Am J Physiol. 1997; 273: H1933–1940.[Medline] [Order article via Infotrieve]
107. Hirose M, Furukawa Y, Kurogouchi F, Nakajima K, Miyashita Y, Chiba S. C-type natriuretic peptide increases myocardial contractility and sinus rate mediated by guanylyl cyclase-linked natriuretic peptide receptors in isolated, blood-perfused dog heart preparations. J Pharmacol Exp Ther. 1998; 286: 70–76.
108. Wollert KC, Yurukova S, Kilic A, Begrow F, Fiedler B, Gambaryan S, Walter U, Lohmann SM, Kuhn M. Increased effects of C-type natriuretic peptide on contractility and calcium regulation in murine hearts overexpressing cyclic GMP-dependent protein kinase i. Br J Pharmacol. 2003; 140: 1227–1236.[CrossRef][Medline] [Order article via Infotrieve]
109. Layland J, Li JM, Shah AM. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J Physiol. 2002; 540: 457–467.
110. Wen JF, Cui X, Jin JY, Kim SM, Kim SZ, Kim SH, Lee HS, Cho KW. High and low gain switches for regulation of cAMP efflux concentration: Distinct roles for particulate gc- and soluble GC-cGMP-PDE3 signaling in rabbit atria. Circ Res. 2004; 94: 936–943.
111. Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA. cGMP catabolism by PDE5a regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res. 2004.
112. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest. 2001; 107: 975–984.[Medline] [Order article via Infotrieve]
113. Kishimoto I, Rossi K, Garbers DL. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad Sci U S A. 2001; 98: 2703–2706.
114. Wollert KC, Fiedler B, Gambaryan S, Smolenski A, Heineke J, Butt E, Trautwein C, Lohmann SM, Drexler H. Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects of nitric oxide in cardiomyocytes. Hypertension. 2002; 39: 87–92.
115. Zahabi A, Picard S, Fortin N, Reudelhuber TL, Deschepper CF. Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse hearts. J Biol Chem. 2003; 278: 47694–47699.
116. Hassan MA, Ketat AF. Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T. BMC Pharmacol. 2005; 5: 10.[CrossRef][Medline] [Order article via Infotrieve]
117. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005; 11: 214–222.[CrossRef][Medline] [Order article via Infotrieve]
118. Das A, Ockaili R, Salloum F, Kukreja RC. Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits. Am J Physiol Heart Circ Physiol. 2004; 286: H1455–H1460.
119. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem. 2005; 280: 12944–12955.
120. Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res. 2003; 92: 595–597.
121. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation. 2005; 111: 1601–1610.
122. Conti M. Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol Endocrinol. 2000; 14: 1317–1327.
123. Sonnenburg WK, Mullaney PJ, Beavo JA. Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. J Biol Chem. 1991; 266: 17655–17661.
This article has been cited by other articles:
 |
|
 |
|
  T. Reffelmann and R. A. Kloner Phosphodiesterase 5 inhibitors: are they cardioprotective? Cardiovasc Res, July 15, 2009; 83(2): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Krieg, Y. Liu, T. Rutz, C. Methner, X.-M. Yang, T. Dost, S. B. Felix, J.-P. Stasch, M. V. Cohen, and J. M. Downey BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts Eur. Heart J., July 1, 2009; 30(13): 1607 - 1613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tojima, R. Itofusa, and H. Kamiguchi The Nitric Oxide-cGMP Pathway Controls the Directional Polarity of Growth Cone Guidance via Modulating Cytosolic Ca2+ Signals J. Neurosci., June 17, 2009; 29(24): 7886 - 7897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Diebold, T. Djordjevic, A. Petry, A. Hatzelmann, H. Tenor, J. Hess, and A. Gorlach Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2 Circ. Res., May 22, 2009; 104(10): 1169 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. A. Mohamed, D. Oceandy, S. Prehar, N. Alatwi, Z. Hegab, F. M. Baudoin, A. Pickard, A. O. Zaki, R. Nadif, E. J. Cartwright, et al. Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the {beta}-Adrenergic Signal in the Myocardium J. Biol. Chem., May 1, 2009; 284(18): 12091 - 12098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Adderley, E. A. Dufaux, M. Sridharan, E. A. Bowles, M. S. Hanson, A. H. Stephenson, M. L. Ellsworth, and R. S. Sprague Iloprost- and isoproterenol-induced increases in cAMP are regulated by different phosphodiesterases in erythrocytes of both rabbits and humans Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1617 - H1624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kruger, S. Kotter, A. Grutzner, P. Lang, C. Andresen, M. M. Redfield, E. Butt, C. G. dos Remedios, and W. A. Linke Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs Circ. Res., January 2, 2009; 104(1): 87 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. William, E. J. Hamilton, A. Garcia, H. Bundgaard, K. K. M. Chia, G. A. Figtree, and H. H. Rasmussen Natriuretic peptides stimulate the cardiac sodium pump via NPR-C-coupled NOS activation Am J Physiol Cell Physiol, April 1, 2008; 294(4): C1067 - C1073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ikeda, M. Hoshijima, and K. R. Chien Toward Biologically Targeted Therapy of Calcium Cycling Defects in Heart Failure Physiology, February 1, 2008; 23(1): 6 - 16. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||