Reviews |
From the Department of Biomedical Sciences (W.G.P.), University of Guelph, Guelph, Ontario, Canada; Department of Physiology and Biophysics (R.J.S.), College of Medicine, University of Illinois at Chicago, Chicago, Ill.
Correspondence to R. John Solaro, PhD, Department of Physiology and Biophysics, (M/C 901), College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612-7342. E-mail SolaroRJ{at}uic.edu
This Review is part of a thematic series on Regulatory Signaling by Thin Filament Modulation, which includes the following articles:
Modulation of Thin Filament Activation by Breakdown or Isoform Switching of Thin Filament Proteins: Physiological and Pathological Implications
Covalent and Noncovalent Modification of Thin Filament Action: The Essential Role of Troponin in Cardiac Muscle Regulation
At the Crossroads of Myocardial Signaling: The Role of Z-Discs in Intracellular Signaling and Cardiac Function
Modulation of Thin Filament Activation by Crossbridges
R. John Solaro Guest Editor
| Abstract |
|---|
|
|
|---|
Key Words: signal transduction sarcomere diastolic function myopathies hypertrophy
| Introduction |
|---|
|
|
|---|
100-nm wide Z-line, situated at the center of the I-band (Figure 1).2 As also illustrated in the electron-micrograph in Figure 1, cross sections of cardiac muscle preparations reveal two structural states of the Z-disc, a predominant basket weave pattern and a small square pattern. The ability of Z-discs to alter their lattice network in conjunction with changes in actin-myosin interaction supports the hypothesized role for Z-discs as mechanosensors.3,4 The striking basket weave pattern is likely to arise at least in part from patterns of distribution of the first set of Z-disc proteins that we discuss: actin and its barbed end capping protein, CapZ,
-actinin, the N-terminal region of titin and its capping protein telethonin, the C-terminal region of nebulette, and obscurin.
|
About 100-nm regions of the barbed ends of actin filaments from each half sarcomere overlap within the Z-disc regions as illustrated in Figure 2, and are capped by CapZ, an actin capping protein. The actin capping protein is a heterodimer composed of an
- and ß-subunit. In cardiac myocytes actin capping protein, which is composed of the ß1-subunit localizes to the Z-line, and ß2-subunit containing actin capping protein localizes to the intercalated disc and cell periphery.5 Whereas both populations of actin capping protein bind the barbed ends of actin filaments with equal affinities and kinetics6 the function of ß1-containing actin capping protein is to anchor sarcomeric actin to Z-disc.7 The exact nature of the interaction between actin capping protein, filamentous actin, and other Z-line proteins is unknown, although interaction between
-actinin and actin capping protein has been demonstrated.8
|
-Actinin is a critical Z-disc protein, which cross-links sarcomeric actin and plays a role in reversing the polarity of the actins on either side of the Z-line.
-Actinin consists of homodimers arranged antiparallel with the C-terminal regions bound to adjacent parallel actin filaments within the Z-disc (Figure 1).9 Although
-actinin has been viewed as the major Z-disc protein in all striated muscles, it accounts for less than 20% of the total protein content of Z-discs.10 Moreover, as will be described,
-actinin interacts with a number of proteins, indicating that actin cross-linking and reversal of polarity requires additional proteins. Two of these proteins are titin and nebulette.
As illustrated in Figure 1, a major connection of the Z-disc with the rest of the sarcomere occurs through its interaction with the giant filamentous protein titin (connectin), which is >3 million kDa.11,12 A truncated form of titin (
700 kDa), which we discuss later together with obscurin, has also been reported to be expressed in cardiac muscle.12 Titin is important as a template in assembly of the thick filament by acting as a molecular ruler, and is also responsible in large part for the passive tension of cardiac myocytes above slack length and for the restoration of length below slack length. Thus, titin is a bidirectional spring. N-terminal domains of titin insert into the Z-disc where the titin molecules from opposing sarcomeres overlap.1315 The N-terminus of titin is capped by the protein, T-cap (telethonin).14,16,17 T-cap is a 19-kDa protein with a unique structure and so far is restricted in expression to heart and skeletal muscle. The region of titin in the Z-disc interacts with actin through 45 amino acid domains called Z-repeats. This region of titin has also been demonstrated to bind to the N-terminal regions of
-actinin,1821 although not all studies were able to demonstrate this binding.13,22 Alternative splicing of Z-repeats provides a mechanism for diversification of Z-disc structure.18 Gregorio et al14 reported that Z-repeats (Z1 and Z2) bind T-cap in the periphery of the Z-disc. It is of interest that the regions of T-cap that do not interact with the Z-repeats of titin are rich in basic proteins and Ser/Thr residues and are predicted to be modified by phosphorylation. In fact, it has been reported that a C-terminal kinase domain of titin phosphorylates telethonin during myofibrillogenesis.23 Whether the state of phosphorylation of T-cap is functionally significant in the mature Z-disc remains unknown. The C-terminus of titin attaches to the M-line of the sarcomere. In spanning the full half-sarcomere, titin makes contact with the head-neck interface of crossbridges through its interaction with myosin binding protein C (MyBP-C), and possibly thin filament actins outside the Z-disc. As discussed below, interactions of titin with MyBP-C have been proposed as an important element in length-dependent activation of the myofilaments and Starlings law of the heart.24,25
The passive tension of cardiac myocytes, which is a critical determinant of the operating sarcomere length and of forces determining diastolic pressure, resides largely in the stress-strain relations of the titin molecule. The molecular spring is localized in PEVK domains, in which 75% of the amino acids are proline, glutamic acid, valine, and lysine. The PEVK region, which is flanked by immunoglobulin-like (Ig) repeats, has also been demonstrated to bind to actin, by a Ca2+-dependent mechanism involving the Ca2+ binding protein S100A1, which is described in more detail later.26 This property appears to be specialized to the cardiac titin isoform (N2B) that is predominant in small rodent hearts and is a major component of the human heart population that includes another isoform (N2BA). Determinants of passive tension thus appear to reside not only in series attachments of titin with proteins of the Z-disc, but also in the interaction with I-band actins that run parallel to titin. Communications to and from titin and Z-disc proteins provide a sensing mechanism for the cardiac myocytes to sense strain. A role for titin in biochemical signaling cascades is also indicated by the presence of multiple phosphorylation sites, some of which are specialized in the cardiac isoform and affect passive tension.27 In addition, the C-terminal domain of titin has protein kinase activity.
Nebulette (107 kDa), which is the cardiac homologue of the 900-kDa skeletal muscle protein nebulin, is another relatively abundant protein associated with the Z-discs in cardiac myocytes.2830 Whereas ample evidence indicates that nebulin acts as a molecular ruler for skeletal muscle thin filaments.,3133 the much smaller size of nebulette makes it unlikely that it plays a comparable role in cardiac muscle.28,33 Nebulin and nebulette share sequence similarities and contain 35 residue repeats (nebulin repeats), a linker domain, and a C-terminal Src homology 3 (SH3) domain that also binds to
-actinin.29,34 The nebulin repeats bind actin with high affinity, but there is also evidence that nebulette motifs bind troponin T and tropomyosin.35 The ability of nebulette to bind both actin and
-actinin raises the possibility that nebulette may anchor sarcomeric actin to
-actinin.29 The presence of SH3 domains, which are highly conserved and composed of 50 to 70 residues that commonly link to proline-rich regions of proteins important in signal transduction, indicates a role of nebulette in signaling. Yet, this is not the case with the binding partner
-actinin, which is not rich in prolines. As pointed out by Moncman and Wang,29 other proline-rich binding partners may play a role. It is intriguing that SH3 domains have also been implicated as important in vesicular trafficking.36 Although of considerable interest, whether and how the SH3 domains of nebulette participate in signal transduction or vesicular trafficking remains unknown. By targeted disruption of nebulette, Moncman and Wang30 have provided evidence that nebulette is important in both the structure, by aiding in myofibrillar organization and possibly as a determinant of Z-band width, and function, by determining the integrity of the thin filaments.
Obscurin (
800 kDa) is a recently discovered Z-disc protein that shares similarities with titin in having tandem Ig domains in an elastic region.12 Two of these Ig domains located in the C-terminal region are specific to obscurin and interact with the N-terminal region of titin in the Z-disc. Stretching of cardiac myocytes has been demonstrated to move epitopes localized to titin and obscurin, indicating that both filaments are extensible.12 Apart from its structural role in the protein network of the Z-disc, obscurin has the potential for versatile signaling properties that are described later.
| Z-Discs Serve as Mediators of Signaling Cascades Regulated by Cell Strain |
|---|
|
|
|---|
Changes in cell strain sensed by the Z-disc and associated structures occur during a beat and in the short term, with beat-to-beat changes in diastolic volume. The stretch of the myocytes that occurs with the changes in diastolic volume signals an increase in active pressure developed by the myocardium according to Starlings Law. Although Starlings Law is a widely accepted tenet of cardiovascular biology, its underlying molecular mechanism remains elusive. There is substantial evidence that the mechanism involves a length dependence of activation of the myofilaments by Ca2+; as sarcomere length increases between physiological limits, maximum tension increases and so does Ca2+ sensitivity.39 Although the mechanism of the length dependence is not agreed on, one theory is that increases in sarcomere length result in decreases in interfilament spacing, which increase the probability for the reaction of crossbridges with the thin filament.39 This would be expected to occur in a constant volume system. Cazorla et al,24 however, proposed a role for titin in length-dependent activation by a mechanism in which passive stretch of titin regulates interfilament spacing. The idea presented by Cazorla et al24 is that with an oblique arrangement of the extensible region of titin that joins the thin and thick filament (Figure 2), a radial force is generated that modifies interfilament spacing. Integrity in the anchoring of titin to the Z-disc is critical to this attractive hypothesis. However, a role for altered interfilament spacing in Starlings Law has been challenged by data of Konhilas et al,40,41 who could find no correlation between changes in interfilament spacing, as determined using X-ray diffraction, and differences in length-dependent activation among various muscle types. Using transgenesis to specifically replace the thin filament regulatory protein, cardiac troponin I, with slow skeletal troponin I induced a blunting of length-dependent activation that also was not correlated with altered interfilament spacing.41 An alteration in the length dependence of activation by a specific change in the thin filament indicates the complexity of the process. A mechanism that may not require changes in interfilament spacing has been proposed by Helmes et al25 at least for the case of compression at short sarcomere lengths. In this mechanism, when sarcomeres are compressed (a situation simulating the end-systolic to diastolic transition), the response of the myofilaments to Ca2+ is depressed. Proteolysis of titin blunted this reduction in sensitivity to Ca2+ and reduced the rate of restoration of sarcomere length after compression. Thus, alterations in titin isoform composition and passive stiffness, which occur in various acquired and inherited diseases, are likely to be important in modifying Starlings Law.42 The role of Z-disc proteins other than titin in length dependence of activation remains unclear. Z-disc proteins considered so far form an intricate structural network. As with any complex set of interacting components, there is high likelihood that a disturbance of interactions in any one component will affect others in the network.
In the long term, sustained increases in end diastolic volume and cell stretch signal hypertrophic responses leading to cell growth and remodeling.43 The growth may be adaptive as during cardiac development and chronic exercise, or maladaptive leading to cardiac failure and dilatation. Control of adaptive or maladaptive growth of the heart involves a combination of physical and biochemical signals that interconnect the extracellular matrix, the cell surface, sarcomeres, and the nucleus. The desmin network of the cytoskeleton, which links Z-discs to each other in neighboring myofilament bundles, to the sarcolemmal, and to the nuclear envelope,37,38,44 is a key component that serves as a physical link between the Z-disc and the nucleus. Extracellular mechanical stresses alter the spatial arrangement of the desmin network and impact nuclear function, including gene transcription.38,45
The costamere forms a center of communication between the extracellular matrix, the sarcolemma, and the Z-disc.45 Costameres, which are analogues of focal adhesion complexes present in nonmuscle cells, are composed of an assembly of a growing number of proteins, including
-actinin, tailin, vinculin, ankyrin, ß-integrins, dystrophin, and
-actin.45 The costameres are localized around the circumference of the myocytes at regular intervals and in register with the Z-disc of the peripheral myofilament bundles. Desmin, an intermediate filament, forms a major physical link between the costamere and the Z-disc of the sarcomere. Cell surface integrins, which span the sarcolemmal membrane have been identified as mechanosensors in nonmuscle cells46,47 and have a similar role in cardiac myocytes. Cytoplasmic domains of integrins are linked to Z-discs through talin and vinculin, two cytoskeletal proteins.48 Extracellular domains of integrins interact with laminin of the extracellular matrix.49 Changes in the conformation of sarcolemmal integrins could pass through talin and vinculin to Z-disc
-actinin and actin.48 Likewise, dystrophin links cardiac Z-discs to the sarcolemma50 and may provide a route for mechanical signaling to the Z-disc. Although a detailed discussion is beyond the scope of this review, it is important that changes occurring in the extracellular matrix may influence and be influenced by signaling traffic between the costamere, peripheral Z-discs, central Z-discs, and the nucleus.45
Homeostasis in the long-term regulation of the processes that determine the abundance of cardiac cellular components and the relative expression of their isoforms also depend on the integrity of the Z-disc. In pathological states, disturbance in the Z-disc protein network by inherited or acquired diseases or syndromes may have catastrophic effects. In this case, proteins of the Z-disc, which undoubtedly are important in the structural and mechanical stability of the sarcomere, serve as docking sites for transcription factors, Ca2+ signaling proteins, and for kinases and phosphatases that affect function and gene expression. The Z-disc also appears to serve as a way station for proteins that regulate transcription and move between the Z-disc and the nucleus. These properties demonstrate and emphasize the inseparability of the mechanical, structural, and biochemical functions of the Z-disc complex. The discussion regarding the next set of Z-disc proteins reveals this multiplex function of the Z-disc. As illustrated in Figure 2, these proteins include the following: LIM proteins (muscle LIM protein, MLP; actinin-associated LIM protein, ALP), myopallidin, myopodin, cypher (ZASP, oracle), calsarcins, CARP (cardiac restricted ankyrin repeated protein), and the Ca2+ binding protein, S-100.
| Z-Discs as Centers in Signaling Cascades Involving Kinases, Phosphatases, and Ca2+ |
|---|
|
|
|---|
-isoform.59 Two striated musclerestricted proteins named cypher60 and enigma homologue protein61 have also been identified as possible Z-disc anchors of activated PKC. The presence of multiple PKC anchoring proteins at cardiac Z-discs, coupled with immunolocalization studies showing PKC binding at cardiac Z-discs indicates a significant role for Z-discs in the mediation of PKC-dependent signaling. CapZ, the actin capping protein that binds and anchors the barbed ends of the thin filaments to the Z-disc may also play an important role in PKC signaling. Disruption of the interaction between actin filaments and the actin capping protein in the heart impairs myofibrillogenesis,62 produces gross myofibrillar disarray, and yields nonviable offspring.7 The subcellular confinement of the actin capping protein to Z-discs, an important structure in PKC signaling, led us to hypothesize a role for actin capping protein in PKC signaling to the myofilaments. Using a transgenic mouse model in which the Z-discassociated actin capping protein was downregulated in the myocardium, we found that PKC-dependent regulation of myofilament function was abolished.63 Moreover, the reduction in Z-discassociated actin capping protein altered the ability of several PKC isoforms to bind cardiac myofilaments.63 These results provide the first evidence in support of a role for Z-discassociated actin capping protein in the transmission of signals through the PKC pathway, and further advances the hypothesis that the localized region at the thin filament-Z-disc interface is a critical juncture in the PKC signaling cascade.
Cypher-1 and its splice variants (homologues are ZASP and oracle) are Z-disc proteins with an amino-terminal PDZ domain that interacts with
-actinin.64,65 PDZ domains, which contain the signature sequence GLGF, are universally used in all biological systems studied to date as linkers among protein networks.66 They are commonly found in association with SH3 domains, as is the case in the Z-disc protein network, and generally interact with the C-terminal regions of proteins in the network. Importantly, there is evidence that interaction of the PDZ domain with desmin may be dynamically modulated by protein phosphorylation. Cypher-1 also binds nonspecifically to PKC isoforms at its LIM domain.65 LIM is an acronym derived from three genes in which the domain was first described. It is a cysteine-rich motif defined by 50 to 60 amino acids with consensus sequence CX2CX1623HX2CX2CX2CX1621CX2(C/H/D) and is also associated with zinc-binding modules.66,67 A muscle-specific variant (MLP) is a LIM-only protein consisting of two LIM domains with abundant expression in heart.67
-Actininassociated LIM protein (ALP) is another Z-disc protein with LIM and PDZ domains.68 ALP, is a muscle-restricted
-actininassociated LIM domain protein that enhances actin cross-linking by
-actinin, stabilizing the sarcomere during periods of stress. The PDZ domain of ALP interacts with the spectrin-like repeats of
-actinin-2. Although abundant in skeletal muscle, expression levels of ALP are relatively low in heart.69,70 Surprisingly, ALP knockout mice do not display gross histological abnormalities in skeletal muscle, indicating either a subtle role in regulation or redundancy of function of other proteins.68 However, Pashmforoush et al69 reported that transgenic mice deficient in ALP exhibit dysmorphogenesis of the embryonic right ventricle and right ventricular dilated cardiomyopathy.
Z-disc proteins also serve as a scaffold to direct the localization of phosphatases near their substrates. Calsarcin-1 is one of the growing family of striated muscle proteins, which bind to
-actinin at the cardiac Z-disc, and also binds calcineurin, a phosphatase that dephosphorylates NFAT (nuclear factor of activated T-cell).52 Dephosphorylated NFAT enters the nucleus and promotes transcription. Ca2+-calmodulindependent regulation of calcineurin has been implicated as a critical factor in cardiac hypertrophy.71 The Z-disc thus may serve as a scaffold to direct the localization of calcineurin in regulating the state of phosphorylation of NFAT. The strategic location of the Z-disc at the T-tubule-SR interface permits sensing Ca2+ on a beat-to-beat basis. It is significant that the Ca2+ binding protein S-100A1 is also localized to the Z-disc. Calsarcins also coimmunoprecipitate with
-filamin, telethonin, and ZASP (also known as oracle and cypher),72 the significance of these interactions require further study. It is significant that ZASP also binds PKC.
An important developing concept is that the Z-disc serves as a way station for signaling molecules. Along these lines, Liu et al73 report that NFATc is localized to the Z-disc of resting skeletal muscle and translocates to the nucleus after chronic electrical stimulation. Moreover, translocation of calcineurin from the Z-disc to the nucleus has also been reported following a hypertrophic stimulus of cardiac myocytes.74 Other signaling proteins that redistribute in the cell also use the Z-disc as a way station in their travels to and from the nucleus. Myopodin is a
85 kDa protein, which shares homology with synaptopodin, a protein rich in prolines that are evenly distributed along the primary structure.75 A striking feature of myopodin is that it appears to redistribute from the Z-disc to the nucleus.75 In the nucleus, myopodin acts to bundle actin filaments and is thought to play a possible role in mRNA transport. Myopallidin is a 145-kDa protein that links the C-terminal Src homology 3 domain of nebulette and the EF-hand motifs of
-actinin.76 The region of myopallidin engaged in this linkage is within a 90-kDa C-terminal region. The N-terminal region of myopallidin interacts with CARP (cardiac ankyrin repeat protein). CARP had been reported to be a nuclear protein acting to downregulate expression of cardiac genes including troponin C, myosin light chain 2, and atrial natriuretic factor.77,78 In studies performed by Bang et al,76 CARP was variably localized in the sarcoplasm and the nucleus, indicating a movement of CARP between these compartments. The localization of CARP-myopallidin complex was at the center of the I-band within the Z-disc. By overexpressing this N-terminal region that contains the CARP binding domain, Bang et al76 demonstrated a severe disruption of sarcomeric structure. They concluded that apart from a potential role as a docking station for CARP, myopallidin is important in the maintenance of the structural integrity of the sarcomere. A role for myopallidin in maintaining the assembly of the Z-disc and sarcomeric structure is also indicated by data reported by Ma and Wang,79 who demonstrated that the SH3 domain of nebulin binds with proline-rich peptides of the PEVK of titin and also to myopallidin. Whether this occurs in the case of nebulette has not been determined, but seems highly likely.
Obscurin is an excellent example of a multiplex Z-disc protein that is likely to participate in signaling cascades.12 The C-terminal region that interacts with titin also contains an IQ motif that is known be a binding site for calmodulin.80 IQ motifs serve a variety of functions in diverse proteins that may transduce Ca2+ signals but also serve as binding sites for calmodulin independent of Ca2+. The exact function of the IQ motif in obscurin is not clear, but its localization in the region of Ca2+ release in cardiac myocytes indicates a potential role in Ca2+ signaling. Moreover, recent evidence indicates that obscurin may make a physical link with the SR, mediated by ankyrin-1.81 On the basis of data implicating ankyrin-1 in localization of Ca2+ release channels (ryanodine receptors) in the SR, Bagnato et al81 proposed that obscurin may serve as an element in localizing proteins of the SR as well linking the myofilaments to the SR. Ankyrin-1 has also been reported to interact with titin at the Z-disc.82 A C-terminal region of obscurin also is composed of a Rho guanine nucleotide exchange factor domain (RHO-GEF domain or DH domain) that catalyzes GTP-GDP exchange, thereby activating the Rho family of small G-proteins.83 Rho is a small G-proteins involved in a wide variety of functions including cytoskeletal structure, transcriptional control, and cell cycle control.84
The localization of S100 at the Z-disc also indicates a role for the protein network in Ca2+ signaling. In the normal, healthy heart, S100A1 is the preferential isoform in myocardial tissue.85 Because of its subcellular localization to cardiac Z-discs, in close approximation with the myofilaments, a role for S100A1 in the regulation of myofilament function has been proposed. Most et al85 demonstrated that exogenous S100A1 protein significantly decreases myofilament calcium sensitivity without altering maximum force development. These findings are in agreement with those of Adhikari and Wang86 who reported a reduction in skeletal muscle myofilament Ca2+ sensitivity, without a change in maximum activation. Although a link between S100 protein proteins and myofilament regulation is supported by these data, the mechanism by which S100 modulates myofilament function is unknown. Adhikari and Wang86 proposed a mechanism in which S100 binding to actin modulates actin-myosin interaction. Yamasaki et al26 have reported an interaction between S100A1 and the PEVK segment of titin, but not actin. Although Yamasaki et al failed to detect any direct interaction between S100A1 and filamentous actin, these findings raise the possibility that the modification of actin-myosin interaction by S100A1 may be mediated through one or more intermediate proteins. Alternatively, S100 proteins may modify myofilament calcium sensitivity by inhibiting the actions of PKC. Although several studies have described the inhibitory effects of S100B on the actions of PKC,87 there are currently no reported studies investigating the relationship between the myocardial S100A1 isoform and PKC.
| Z-Discs and Mechanoelectric Feedback in Ion Channel Regulation |
|---|
|
|
|---|
The subcellular mechanism through which mechanoelectric feedback is mediated is not well defined. However, recent work implicates cardiac Z-discs in this feedback loop. Furukawa90 and colleagues demonstrated a physical link between the C-terminus of the Z-line protein telethonin and the ß-subunit (MinK) of the delayed rectifier K+ channel (IKs). In cardiac myocytes IKs influences action potential duration by regulating cellular repolarization.91,92 The interactions between IKs, telethonin, and titin forms a complex that directly links the myofibrils with the sarcolemma, providing a circuit for mechanoelectric feedback. Mutations in IKs-encoding genes are associated with several forms of long QT syndromes and most of these mutations lie within the region encoding the telethonin-binding cytoplasmic domain.93
Communication between the myofilaments and sarcolemmal ion channels may also be mediated through a biochemical link. The cardiac Z-disc and its associated components anchor intracellular signaling molecules, including PKC and PKA, that regulate L-type Ca2+ channels.94 Kinases and phosphatases anchored at the Z-discs are placed in close approximation with T-tubular L-type Ca2+ channels, a situation that may facilitate interaction. Although numerous studies have found that L-type Ca2+ channels are substrates of signaling proteins anchored at the Z-line, to date there are no definitive reports showing a direct relationship between Z-line signaling molecules and L-type Ca2+ channels.
| Failure of Signaling at the Z-Discs and Failure of the Heart |
|---|
|
|
|---|
-actinin, demonstrate right ventricular dilated cardiomyopathy.69 Zhou et al64 have proposed cypher as a "linker-strut" that reinforces Z-disc protein interactions. Cypher-null mutant mice also develop severe cardiomyopathy and ventricular dilation.64 Interestingly, the cypher deletion results in abnormal Z-disc structure in contracting muscle, but not in the noncontracting muscle of the embryonic diaphragm, suggesting that cypher is not required for normal genesis of the sarcomere, but is essential to the stabilization of Z-line structure during contraction. Experiments reported by Knöll et al38 provide an explicit example of the connection between altered mechanical stability of the Z-disc and dilated cardiomyopathy. Knöll et al proposed that MLP interaction with T-Cap is a "stretch sensor" complex in mechanotransduction. The basis for this proposal is that defects in this interaction are associated with dilated cardiomyopathy and heart failure linked to an MLP mutation (W4R). Moreover, sarcomeres of MLP-/- mice demonstrated wider Z-discs and misalignment of Z-disc components. The MLP-/- mice also demonstrated altered T-cap location and release from the myofilaments to the cytosolic compartment. However, further studies are required to identify the members of this complex, the nature of their interactions, and to elucidate the mechanistic link between Z-discs, passive stretch, and cardiomyopathy. It is of interest, however, that myostatin a secreted growth factor of the TGF-ß superfamily, also associates with T-Cap (Figure 1),104 and is upregulated in cardiomyocytes after an infarct.105
Members of the S100 family of EF-hand Ca2+-binding proteins have also been identified as intrinsic proteins regulating the hypertrophic process in heart. In cardiac myocytes, S100 proteins associate with Z-discs, intercalated discs, and the SR.105 Anchoring of S100 proteins to the Z-disc may occur through the
-subunit of the actin capping protein106,107 and/or the PEVK fragment of titin.108 Immunohistochemical analysis of failing human hearts has shown a reduction in S100A expression113 and an induction of the normally undetectable S100B.109,110 Tsoporis et al111 hypothesized that the induction of S100B expression was a compensatory response to the overload of the failing heart. To test this idea, they forced the expression of S100B in cardiac myocytes and examined the myocardial response to hypertrophic stimuli. Expression of S100B abolished both the myocardial hypertrophy pursuant with norepinephrine treatment, as well as the induction of genetic markers of hypertrophy.111 These findings are in agreement with the hypothesis that the upregulated expression of S100B is a compensatory response to myocardial stress.
In view of its many interactions in the cytoskeletal network it is not surprising that the integrity of the interaction of desmin at the Z-disc is critical to cellular homeostasis. In cardiac myocytes desmin surrounds and interlinks the Z-discs, as well as forming a web connecting the myofibrils, sarcolemma, costameres, intercalated discs, sarcoplasmic reticulum, T-tubules, and nuclei. The extensive network formed by desmin filaments has been proposed to perform a variety of functions including the regulation of mitochondrial metabolism,112 subcellular structural organization,113 myofibrillogenesis,114 and force development.115 Transgenic mice with a null mutation in the desmin gene develop severe cardiomyopathy,116,117 and several studies have reported desmin-related cardiomyopathies in human populations.118120 The myocardial failure associated with desmin abnormalities is likely the product of increased cellular fragility and impaired structural integrity with a weakened support system. By contrast, Milner et al117 propose a scheme of dilated cardiomyopathic development in which the impairment of force transmission by desmin and other Z-discassociated proteins is a significant contributing factor in the resulting cell death, chamber dilation, and heart failure.
A unique pool of Z-disc dystrophin also appears essential in maintaining the structural and functional integrity of the myocardium. Coding abnormalities and null mutations of the dystrophin protein are the causative factor of muscular dystrophies, including some forms of dilated cardiomyopathy.121 Meng et al122 have found a cardiac exclusive localization of dystrophin to the Z-disc. Although the details of the interaction between dystrophin and cardiac Z-discs are unknown, several reports support the hypothesis of Meng et al122 that dystrophin is anchored at the Z-disc through interactions with actin.123 A deficiency in the Z-discassociated dystrophin is associated with a more severe form of cardiomyopathy, as compared with the cardiac insufficiencies that develop with the loss of sarcolemmal dystrophin. The high correlation between Z-disc dystrophin loss and the cardiac derangements associated with dilated cardiomyopathy provides strong evidence of the functional significance of this unique pool of dystrophin.
| Challenges Facing the Study of the Z-Disc |
|---|
|
|
|---|
| Acknowledgments |
|---|
| Footnotes |
|---|
| References |
|---|
|
|
|---|
2. Goldstein MA, Schroeter JP. Ultrastructure of the heart. In: Page E, Fozzard H, Solaro RJ, eds. Handbook of Physiology: Section 2: The Cardiovascular System, Volume 1: The Heart. New York, NY: Oxford University Press; 2001: 374.
3. Goldstein MA, Michael LH, Schroeter JP, Sass RL. Two structural states of Z-bands in cardiac muscle. Am J Physiol. 1989; 256: H552H559.[Medline] [Order article via Infotrieve]
4. Goldstein MA, Michael LH, Schroeter JP, Sass RL. Structural states in the Z band of skeletal muscle correlate with state of active and passive tension. J Gen Physiol. 1988; 92: 113119.
5. Schafer DA, Korshunova YO, Schroer TA, Cooper JA. Differential localization and sequence analysis of capping protein ß-subunit isoforms of vertebrates. J Cell Biol. 1994; 127: 453465.
6. Schafer DA, Jennings PB, Cooper JA. Dynamics of capping protein and actin assembly in vitro: uncapping barbed ends by polyphosphoinositides. J Cell Biol. 1996; 135: 169179.
7. Hart MC, Cooper JA. Vertebrate isoforms of actin capping protein ß have distinct functions In vivo. J Cell Biol. 1999; 147: 12871298.
8. Papa I, Astier C, Kwiatek O, Raynaud F, Bonnal C, Lebart MC, Roustan C, Benyamin Y.
Actinin-CapZ, an anchoring complex for thin filaments in Z-line. J Muscle Res Cell Motil. 1999; 20: 187197.[CrossRef][Medline]
[Order article via Infotrieve]
9. Stromer MH, Goll DE. Studies on purified
-actinin, II: electron microscopic studies on the competitive binding of
-actinin and tropomyosin to Z-line extracted myofibrils. J Mol Biol. 1972; 67: 489494.[CrossRef][Medline]
[Order article via Infotrieve]
10. Robson RM, Goll DE, Arakawa N, Stromer M. Purification and properties of
-actinin from rabbit skeletal muscle. Biochim Biophys Acta. 1970; 200: 296318.[Medline]
[Order article via Infotrieve]
11. Wang K, Ramirez-Mitchell R, Palter D. Titin is an extraordinarily long, flexible, and slender myofibrillar protein. Proc Natl Acad Sci U S A. 1984; 81: 36853689.
12. Bang ML, Centner T, Fornoff F, Grach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S. The complete gene sequence of titin expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res. 2001; 89: 10651072.
13. Gautel M, Goulding D, Bullard B, Weber K, Furst DO. The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers. J Cell Sci. 1996; 109: 27472754.[Abstract]
14. Gregorio CC, Trombitas K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S. The NH2 terminus of titin spans the Z-disk: its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity. J Cell Biol. 1998; 143: 10131027.
15. Yajima H, Ohtsuka H, Kawamura Y, Kume H, Murayama T, Abe H, Kimura S, Maruyama K. A 11.5-kb 5'-terminal cDNA sequence of chicken breast muscle connectin/titin reveals its Z line binding region. Biochem Biophys Res Commun. 1996; 223: 160164.[CrossRef][Medline] [Order article via Infotrieve]
16. Mues A, van der Ven PF, Young P, Furst DO, Gautel M. Two immunoglobulin-like domains of the Z-disk portion of titin interact in a conformation-dependent way with telethonin. FEBS Lett. 1998; 428: 111114.[CrossRef][Medline] [Order article via Infotrieve]
17. Faulkner G, Lanfranchi G, Valle G. Telethonin and other new proteins of the Z-disc of skeletal muscle. IUBMB Life. 2001; 51: 275282.[Medline] [Order article via Infotrieve]
18. Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Labeit D, Linke WA, Suzuki K, Labeit S. Tissue-specific expression and
-actinin binding properties of the Z-disk titin: implications for the nature of vertebrate Z-disks. J Mol Biol. 1997; 270: 688695.[CrossRef][Medline]
[Order article via Infotrieve]
19. Ohtsuka H, Yajima H, Maruyama K, Kimura S. Binding of the N-terminal 63 kDa portion of connectin/titin to
-actinin as revealed by the yeast two-hybrid system. FEBS Lett. 1997; 401: 6567.[CrossRef][Medline]
[Order article via Infotrieve]
20. Ohtsuka H, Yajima H, Maruyama K, Kimura S. The N-terminal Z repeat 5 of connectin/titin binds to the C-terminal region of
-actinin. Biochem Biophys Res Commun. 1997; 235: 13.[CrossRef][Medline]
[Order article via Infotrieve]
21. Turnacioglu KK, Mittal B, Sanger JM, Sanger JW. Partial characterization of zeugmatin indicates that it is part of the Z-band region of titin. Cell Motil Cytoskeleton. 1996; 34: 108121.[CrossRef][Medline] [Order article via Infotrieve]
22. Nave R, Furst DO, Weber K. Interaction of
-actinin and nebulin in vitro: support for the existence of a fourth filament system in skeletal muscle. FEBS Lett. 1990; 269: 163166.[CrossRef][Medline]
[Order article via Infotrieve]
23. Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Furst DO, Wilmanns M, Gautel M. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature. 1998; 395: 863869.[CrossRef][Medline] [Order article via Infotrieve]
24. Cazorla O, Vassort G, Garnier D, Le Guennec JY. Length modulation of active force in rat cardiac myocytes: is titin the sensor? J Mol Cell Cardiol. 1999; 31: 12151227.[CrossRef][Medline] [Order article via Infotrieve]
25. Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003; 121: 97110.
26. Yamansaki R, Berri M, Wu Y, Trombitas K, McNabb M, Kellermayer MS, Witt C, Labeit D, Labeit S, Greaser M, Granzier H. Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys J. 2001; 81: 22972313.[Medline] [Order article via Infotrieve]
27. Yamasaki R, Wu Y, McNabb M, Greaser M, Labeit S, Granzier H. Protein kinase A phosphorylates titins cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res. 2002; 90: 11811188.
28. Moncman CL, Wang K. Nebulette: a 107 kD nebulin-like protein in cardiac muscle. Cell Motil Cytoskeleton. 1995; 32: 205225.[CrossRef][Medline] [Order article via Infotrieve]
29. Moncman CL, Wang K. Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains. Cell Motil Cytoskeleton. 1999; 44: 122.[CrossRef][Medline] [Order article via Infotrieve]
30. Moncman CL, Wang K. Architecture of the thin filament-Z-line junction: lessons from nebulette and nebulin homologies. J Muscle Res Cell Motil. 2000; 21: 153169.[CrossRef][Medline] [Order article via Infotrieve]
31. Kruger M, Wright J, Wang K. Nebulin as a length regulator of thin filaments of vertebrate skeletal muscles: correlation of thin filament length, nebulin size, and epitope profile. J Cell Biol. 1991; 115: 97107.
32. Labeit S, Kolmerer B. The complete primary structure of human nebulin and its correlation to muscle structure. J Mol Biol. 1995; 248: 308315.[Medline] [Order article via Infotrieve]
33. Millevoi S, Trombitas K, Kolmerer B, Kostin S, Schaper J, Pelin K, Granzier H, Labeit S. Characterization of nebulette and nebulin and emerging concepts of their roles for vertebrate Z-disks. J Mol Biol. 1998; 282: 111123.[CrossRef][Medline] [Order article via Infotrieve]
34. Wang K, Knifer M, Huang QQ, van Heerden A, Hsu LC, Gutierrez G, Quian XL, Stedman H. Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture: sequence motifs and affinity profiles of tandem repeats and terminal SH3. J Biol Chem. 1996; 271: 43044314.
35. Ogut O, Hossain MM, Jin J-P. Interactions between nebulin-like motifs and thin filament regulatory proteins. J Biol Chem. 2003; 278: 30893087.
36. McPherson PS. Regulatory role of SH3 domain-mediated protein-protein interactions in synaptic vesicle endocytosis. Cell Signal. 1999; 11: 229238.[CrossRef][Medline] [Order article via Infotrieve]
37. Epstein ND, Davis JS. Sensing stretch is fundamental. Cell. 2003; 112: 147150.[CrossRef][Medline] [Order article via Infotrieve]
38. Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002; 111: 943955.[CrossRef][Medline] [Order article via Infotrieve]
39. Fuchs F. The Frank-Starling relationship: cellular and molecular mechanisms. In: RJSolaro, RLMoss, eds. Molecular Control Mechanisms in Striated Muscle Contraction. Dordrecht, Netherlands: Kluwer Academic Publishers; 2002: 379416.
40. Konhilas JP, Irving TC, De Tombe PP. Frank-Starling law of the heart and the cellular mechanisms of length-dependent activation. Pflugers Arch. 2002; 445: 305310.[CrossRef][Medline] [Order article via Infotrieve]
41. Konhilas JP, Irving TC, Wolska BM, Martin AF, Jweid E, Solaro RJ, deTombe PP. Troponin I in the heart: influence on length-dependent activation and inter-filament spacing. J Physiol (Lond). 2003; 3: 951961.
42. Hein S, Schaper J. Weakness of a giant: mutation of the sarcomeric protein titin. Trends Mol Med. 2002; 8: 311313.[CrossRef][Medline] [Order article via Infotrieve]
43. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol. 2003; 65: 4579.[CrossRef][Medline] [Order article via Infotrieve]
44. Lockard VG, Bloom S. Trans-cellular desmin-lamin B intermediate filament network in cardiac myocytes. J Mol Cell Cardiol. 1993; 25: 303309.[CrossRef][Medline] [Order article via Infotrieve]
45. Ervasti JM. Costameres: the Achilles heel of Herculean muscle. J Biol Chem. 2003; 278: 1359113594.
46. Ingber D. Integrins as mechanochemical transducers. Curr Opin Cell Biol. 1991; 3: 841848.[CrossRef][Medline] [Order article via Infotrieve]
47. Loftus JC, Smith JW, Ginsberg MH. Integrin-mediated cell adhesion: the extracellular face. J Biol Chem. 1994; 269: 2523525238.
48. Heling A, Zimmermann R, Kostin S, Maeno Y, Hein S, Devaux B, Bauer E, Klovekorn WP, Schlepper M, Schaper W, Schaper J. Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circ Res. 2000; 86: 846853.
49. Ross RS, Borg TK. Integrins and the myocardium. Circ Res. 2001; 88: 11121129.
50. Hance JE, Fu SY, Watkins SC, Beggs AH, Michalak M.
-Actinin-2 is a new component of the dystrophin-glycoprotein complex. Arch Biochem Biophys. 1999; 365: 216222.[CrossRef][Medline]
[Order article via Infotrieve]
51. Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science. 1997; 278: 20752080.
52. Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A. 2000; 97: 1463214637.
53. Sim AT, Scott JD. Targeting of PKA, PKC and protein phosphatases to cellular microdomains. Cell Calcium. 1999; 26: 209217.[CrossRef][Medline] [Order article via Infotrieve]
54. Disatnik MH, Buraggi G, Mochly-Rosen D. Localization of protein kinase C isozymes in cardiac myocytes. Exp Cell Res. 1994; 210: 287297.[CrossRef][Medline] [Order article via Infotrieve]
55. Huang XP, Pi Y, Lokuta AJ, Greaser ML, Walker JW. Arachidonic acid stimulates protein kinase C-
redistribution in heart cells. J Cell Sci. 1997; 110: 16251634.[Abstract]
56. Robia SL, Ghanta J, Robu VG, Walker JW. Localization and kinetics of protein kinase C-
anchoring in cardiac myocytes. Biophys J. 2001; 80: 21402151.[Medline]
[Order article via Infotrieve]
57. Csukai M, Chen CH, De Matteis MA, Mochly-Rosen D. The costamere protein ß'-COP, a selective binding protein (RACK) for protein kinase C
. J Biol Chem. 1997; 272: 2920029206.
58. Blobe GC, Stribling DS, Fabbro D, Stabel S, Hannun YA. Protein kinase C ßII specifically binds to and is activated by F-actin. J Biol Chem. 1996; 271: 1582315830.
59. Prekeris R, Hernandez RM, Mayhew MW, White MK, Terrian DM. Molecular analysis of the interactions between protein kinase C-
and filamentous actin. J Biol Chem. 1998; 273: 2679026798.
60. Zhou Q, Ruiz-Lozano P, Martone ME, Chen J. Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to
-actinin-2 and protein kinase C. J Biol Chem. 1999; 274: 1980719813.
61. Nakagawa N, Hoshijima M, Oyasu M, Saito N, Tanizawa K, Kuroda S. ENH, containing PDZ and LIM domains, heart/skeletal muscle-specific protein, associates with cytoskeletal proteins through the PDZ domain. Biochem Biophys Res Commun. 2000; 272: 505512.[CrossRef][Medline] [Order article via Infotrieve]
62. Schafer DA, Hug C, Cooper JA. Inhibition of CapZ during myofibrillogenesis alters assembly of actin filaments. J Cell Biol. 1995; 128: 6170.
63. Pyle WG, Hart MC, Cooper JA, Sumandea MP, de Tombe PP, Solaro RJ. Actin capping protein: an essential element in protein kinase signaling to the myofilaments. Circ Res. 2002; 90: 12991306.
64. Zhou Q, Ruiz-Lozano P, Martone ME, Chen J. Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to
-actinin-2 and protein kinase C. J Biol Chem. 1999; 274: 1980719813.
65. Huang C, Zhou Q, Liang P, Hollander MS, Sheikh F, Li X, Greaser M, Shelton GD, Evans S, Chen J. Characterization and in vivo functional analysis of splice variants of cypher. J Biol Chem. 2003; 278: 73607365.
66. Fan J-S, Zhang M. Signaling complex organization by PDZ domains. Neurosignals. 2002; 11: 315321.[CrossRef][Medline] [Order article via Infotrieve]
67. Arber S, Halder G, Caroni P. Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation. Cell. 1994; 79: 221231.[CrossRef][Medline] [Order article via Infotrieve]
68. Jo K, Rutten B, Bunn RC, Bredt DS. Actinin-associated LIM protein-deficient mice maintain normal development and structure of skeletal muscle. Mol Cell Biol. 2001; 21: 16821687.
69. Pashmforoush M, Pomies P, Peterson KL, Kubalak S, Ross J Jr, Hefti A, Aebi U, Beckerle MC, Chien KR. Adult mice deficient in actinin-associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy. Nat Med. 2001; 7: 591597.[CrossRef][Medline] [Order article via Infotrieve]
70. Xia H, Winokur ST, Kuo WL, Altherr MR, Bredt DS. Actinin-associated LIM protein: identification of a domain interaction between PDZ and spectrin-like repeat motifs. J Cell Biol. 1997; 139: 507515.
71. Olson EN, Williams RS. Calcineurin signaling and muscle remodeling. Cell. 2000; 101: 689692.[CrossRef][Medline] [Order article via Infotrieve]
72. Frey N, Olson EN. Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem. 2002; 277: 1399814004.
73. Liu Y, Cseresnyes Z, Randall WR, Schneider MF. Activity-dependent nuclear translocation and intranuclear distribution of NFATc in adult skeletal muscle fibers. J Cell Biol. 2001; 155: 2739.
74. Zou Y, Yao A, Zhu W, Kudoh S, Hiroi Y, Shimoyama M, Uozumi H, Kohmoto O, Takahashi T, Shibasaki F, Nagai R, Yazaki Y, Komuro I. Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation. 2001; 104: 102108.
75. Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol. 2001; 155: 393404.
76. Bang ML, Mudry RE, McElhinny AS, Trombitas K, Geach AJ, Yamasaki R, Sorimachi H, Granzier H, Gregorio CC, Labeit S. Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies. J Cell Biol. 2001; 153: 413427.
77. Jeyaseelan R, Poizat C, Baker RK, Abdishoo S, Isterabadi LB, Lyons GE, Kedes L. A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. J Biol Chem. 1997; 272: 2280022808.
78. Zou Y, Evans S, Chen J, Kuo HC, Harvey RP, Chien KR. CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. Development. 1997; 124: 793804.[Abstract]
79. Ma K, Wang K. Interaction of nebulin SH3 domain with titin PEVK and myopalladin: implications for the signaling and assembly role of titin and nebulin. FEBS Lett. 2002; 532: 273278.[CrossRef][Medline] [Order article via Infotrieve]
80. Bahler M, Rhoads A. Calmodulin signaling via the IQ motif. FEBS Lett. 2002; 513: 107113.[CrossRef][Medline] [Order article via Infotrieve]
81. Bagnato P, Barone V, Giacomello E, Rossi D, Sorrentino V. Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles. J Cell Biol. 2003; 160: 245253.
82. Kontrogianni-Konstantopoulous A, Bloch RJ. The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin. J Biol Chem. 2003; 278: 39853991.
83. Young P, Ehler E, Gautel M. Obscurin, a giant sarcomere Rho guanine nucleotide exchange factor protein involved in sarcomere assembly. J Cell Biol. 2001; 154: 123136.
84. Clerk A, Sugden PH. Small guanine nucleotide-binding proteins and myocardial hypertrophy. Circ Res. 2000; 86: 10191023.
85. Most P, Bernotat J, Ehlermann P, Pleger ST, Reppel M, Borries M, Niroomand F, Pieske B, Janssen PM, Eschenhagen T, Karczewski P, Smith GL, Koch WJ, Katus HA, Remppis A. S100A1: a regulator of myocardial contractility. Proc Natl Acad Sci U S A. 2001; 98: 1388913894.
86. Adhikari BB, Wang K. S100A1 modulates skeletal muscle contraction by desensitizing calcium activation of isometric tension, stiffness and ATPase. FEBS Lett. 2001; 497: 9598.[CrossRef][Medline] [Order article via Infotrieve]
87. Sheu FS, Azmitia EC, Marshak DR, Parker PJ, Routtenberg A. Glial-derived S100b protein selectively inhibits recombinant ß protein kinase C (PKC) phosphorylation of neuron-specific protein F1/GAP43. Brain Res Mol Brain Res. 1994; 21: 6266.[Medline] [Order article via Infotrieve]
88. Lab MJ, Taggart P, Sachs F. Mechano-electric feedback. Cardiovasc Res. 1996; 32: 12.[CrossRef][Medline] [Order article via Infotrieve]
89. Taggart P. Mechano-electric feedback in the human heart. Cardiovasc Res. 1996; 32: 3843.[CrossRef][Medline] [Order article via Infotrieve]
90. Furukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, Labeit S, Inagaki N, Gregorio CC. Specific interaction of the potassium channel ß-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system. J Mol Biol. 2001; 313: 775784.[CrossRef][Medline] [Order article via Infotrieve]
91. Freeman LC, Kass RS. Expression of a minimal K+ channel protein in mammalian cells and immunolocalization in guinea pig heart. Circ Res. 1993; 73: 968973.
92. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current: differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990; 96: 195215.
93. January CT, Gong Q, Zhou Z. Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2. J Cardiovasc Electrophysiol. 2000; 11: 14131418.[CrossRef][Medline] [Order article via Infotrieve]
94. Kamp TJ, Hell JW. Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circ Res. 2000; 87: 10951102.
95. Bowling N, Walsh RA, Song G, Estridge T, Sandusky GE, Fouts RL, Mintze K, Pickard T, Roden R, Bristow MR, Sabbah HN, Mizrahi JL, Gromo G, King GL, Vlahos CJ. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation. 1999; 99: 384391.
96. Solaro RJ, Wolska, BM, Arteaga G, Martin AF, Buttrick P, deTombe P. Modulation of thin filament activity in long and short term regulation of cardiac function. In: RJSolaro, RLMoss, eds. Molecular Control Mechanisms in Striated Muscle Contraction. Dordrecht, Netherlands: Kluwer Academic Publishers; 2002: 291327.
97. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93: 215228.[CrossRef][Medline] [Order article via Infotrieve]
98. Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002; 30: 201204.[CrossRef][Medline] [Order article via Infotrieve]
99. Wu Y, Labeit S, Lewinter MM, Granzier H Titin: an endosarcomeric protein that modulates myocardial stiffness in DCM. J Card Fail. 2002; 8: S276S286.[CrossRef][Medline] [Order article via Infotrieve]
100. Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999; 262: 411417.[CrossRef][Medline] [Order article via Infotrieve]
101. Kimura A, Ito-Satoh M, Hayashi T, Takahashi M, Arimura T. Molecular etiology of idiopathic cardiomyopathy in Asian populations. J Cardiol. 2001; 37: 139146.[Medline] [Order article via Infotrieve]
102. Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science. 1998; 280: 750752.
103. Olson TM, Doan TP, Kishimoto NY, Whitby FG, Ackerman MJ, Fananapazir L. Inherited and de novo mutations in the cardiac actin gene cause hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2000; 32: 16871694.[CrossRef][Medline] [Order article via Infotrieve]
104. Nicholas G, Thomas M, Langley B, Somers W, Patel K, Demp CF, Sharma M, Kambadur R. Titin-cap associates with, and regulates secretion of, myostatin. J Cell Physiol. 2002; 193: 120131.[CrossRef][Medline] [Order article via Infotrieve]
105. Sharma M, Kambadur R, Matthews KG, Somers WG, Devlin GP, Conaglen JV, Fowke PJ, Bass JJ. Myostatin, a transforming growth factor-ß superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct. J Cell Physiol. 1999; 180: 19.[CrossRef][Medline] [Order article via Infotrieve]
106. Ivanenkov VV, Dimlich RV, Jamieson GA, Jr. Interaction of S100a0 protein with the actin capping protein, CapZ: characterization of a putative S100a0 binding site in CapZ
-subunit. Biochem Biophys Res Commun. 1996; 221: 4650.[CrossRef][Medline]
[Order article via Infotrieve]
107. Kilby PM, Van Eldik LJ, Roberts GC. Identification of the binding site on S100B protein for the actin capping protein CapZ. Protein Sci. 1997; 6: 24942503.[Medline] [Order article via Infotrieve]
108. Yamasaki R, Berri M, Wu Y, Trombitas K, McNabb M, Kellermayer MS, Witt C, Labeit D, Labeit S, Greaser M, Granzier H. Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys J. 2001; 81: 22972313.[Medline] [Order article via Infotrieve]
109. Remppis A, Greten T, Schafer BW, Hunziker P, Erne P, Katus HA, Heizmann CW. Altered expression of the Ca2+-binding protein S100A1 in human cardiomyopathy. Biochim Biophys Acta. 1996; 1313: 253257.[Medline] [Order article via Infotrieve]
110. Kahn HJ, Baumal R, Van Eldik LJ, Dunn RJ, Marks A. Immunoreactivity of S100ß in heart, skeletal muscle, and kidney in chronic lung disease: possible induction by cAMP. Mod Pathol. 1991; 4: 698701.[Medline] [Order article via Infotrieve]
111. Tsoporis JN, Marks A, Kahn HJ, Butany JW, Liu PP, OHanlon D, Parker TG. S100ß inhibits
1-adrenergic induction of the hypertrophic phenotype in cardiac myocytes. J Biol Chem. 1997; 272: 3191531921.
112. Kay L, Li Z, Mericskay M, Olivares J, Tranqui L, Fontaine E, Tiivel T, Sikk P, Kaambre T, Samuel JL, Rappaport L, Usson Y, Leverve X, Paulin D, Saks VA. Study of regulation of mitochondrial respiration in vivo: an analysis of influence of ADP diffusion and possible role of cytoskeleton. Biochim Biophys Acta. 1997; 1322: 4159.[Medline] [Order article via Infotrieve]
113. Capetanaki Y. Desmin cytoskeleton: a potential regulator of muscle mitochondrial behavior and function. Trends Cardiovasc Med. 2002; 12: 339348.[CrossRef][Medline] [Order article via Infotrieve]
114. Capetanaki Y, Milner DJ. Desmin cytoskeleton in muscle integrity and function. Subcell Biochem. 1998; 31: 463495.[Medline] [Order article via Infotrieve]
115. Balogh J, Merisckay M, Li Z, Paulin D, Arner A. Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance. Cardiovasc Res. 2002; 53: 439450.
116. Li Z, Colucci-Guyon E, Pincon-Raymond M, Mericskay M, Pournin S, Paulin D, Babinet C. Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Dev Biol. 1996; 175: 362366.[CrossRef][Medline] [Order article via Infotrieve]
117. Milner DJ, Taffet GE, Wang X, Pham T, Tamura T, Hartley C, Gerdes AM, Capetanaki Y. The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function. J Mol Cell Cardiol. 1999; 31: 20632076.[CrossRef][Medline] [Order article via Infotrieve]
118. Ariza A, Coll J, Fernandez-Figueras MT, Lopez MD, Mate JL, Garcia O, Fernandez-Vasalo A, Navas-Palacios JJ. Desmin myopathy: a multisystem disorder involving skeletal, cardiac, and smooth muscle. Hum Pathol. 1995; 26: 10321037.[CrossRef][Medline] [Order article via Infotrieve]
119. Goldfarb LG, Park KY, Cervenakova L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet. 1998; 19: 402403.[CrossRef][Medline] [Order article via Infotrieve]
120. Li D, Tapscoft T, Gonzalez O, Burch PE, Quinones MA, Zoghbi WA, Hill R, Bachinski LL, Mann DL, Roberts R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999; 100: 461464.
121. Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A, Marrosu MG, Cianchetti C, Realdi G, Cao A, Melis MA. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med. 1993; 329: 921925.
122. Meng H, Leddy JJ, Frank J, Holland P, Tuana BS. The association of cardiac dystrophin with myofibrils/Z-disc regions in cardiac muscle suggests a novel role in the contractile apparatus. J Biol Chem. 1996; 271: 1236412371.
123. Hemmings L, Kuhlman PA, Critchley DR. Analysis of the actin-binding domain of
-actinin by mutagenesis and demonstration that dystrophin contains a functionally homologous domain. J Cell Biol. 1992; 116: 13691380.
124. Takeda K, Yu ZX, Qian S, Chin TK, Adelstein RS, Ferrans VJ. Nonmuscle myosin II localizes to the Z-lines and intercalated discs of cardiac muscle and the Z-lines of skeletal muscle. Cell Motil Cytoskeleton. 2000; 46: 5968.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
![]() |
R. Zhang, J. Yang, J. Zhu, and X. Xu Depletion of zebrafish Tcap leads to muscular dystrophy via disrupting sarcomere-membrane interaction, not sarcomere assembly Hum. Mol. Genet., November 1, 2009; 18(21): 4130 - 4140. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. von Nandelstadh, M. Ismail, C. Gardin, H. Suila, I. Zara, A. Belgrano, G. Valle, O. Carpen, and G. Faulkner A Class III PDZ Binding Motif in the Myotilin and FATZ Families Binds Enigma Family Proteins: a Common Link for Z-Disc Myopathies Mol. Cell. Biol., February 1, 2009; 29(3): 822 - 834. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. A. Risebro, R. G. Searles, A. A. D. Melville, E. Ehler, N. Jina, S. Shah, J. Pallas, M. Hubank, M. Dillard, N. L. Harvey, et al. Prox1 maintains muscle structure and growth in the developing heart Development, February 1, 2009; 136(3): 495 - 505. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. P. Walker, T.K. Rajendra, L. Saieva, J. L. Fuentes, L. Pellizzoni, and A. G. Matera SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain Hum. Mol. Genet., November 1, 2008; 17(21): 3399 - 3410. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. J. Solaro Multiplex Kinase Signaling Modifies Cardiac Function at the Level of Sarcomeric Proteins J. Biol. Chem., October 3, 2008; 283(40): 26829 - 26833. [Full Text] [PDF] |
||||
![]() |
M. Tagawa, T. Ueyama, T. Ogata, N. Takehara, N. Nakajima, K. Isodono, S. Asada, T. Takahashi, H. Matsubara, and H. Oh MURC, a muscle-restricted coiled-coil protein, is involved in the regulation of skeletal myogenesis Am J Physiol Cell Physiol, August 1, 2008; 295(2): C490 - C498. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z. Yang, C. F. Browning, H. Hallaq, L. Yermalitskaya, J. Esker, M. R. Hall, A. J. Link, A.-J. L. Ham, M. J. McGrath, C. A. Mitchell, et al. Four and a half LIM protein 1: a partner for KCNA5 in human atrium Cardiovasc Res, June 1, 2008; 78(3): 449 - 457. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Ogata, T. Ueyama, K. Isodono, M. Tagawa, N. Takehara, T. Kawashima, K. Harada, T. Takahashi, T. Shioi, H. Matsubara, et al. MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance Mol. Cell. Biol., May 15, 2008; 28(10): 3424 - 3436. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. A. Linke Sense and stretchability: The role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction Cardiovasc Res, March 1, 2008; 77(4): 637 - 648. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Y. Boateng and P. H. Goldspink Assembly and maintenance of the sarcomere night and day Cardiovasc Res, March 1, 2008; 77(4): 667 - 675. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Faul, A. Dhume, A. D. Schecter, and P. Mundel Protein Kinase A, Ca2+/Calmodulin-Dependent Kinase II, and Calcineurin Regulate the Intracellular Trafficking of Myopodin between the Z-Disc and the Nucleus of Cardiac Myocytes Mol. Cell. Biol., December 1, 2007; 27(23): 8215 - 8227. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Frank, C. Kuhn, M. van Eickels, D. Gehring, C. Hanselmann, S. Lippl, R. Will, H. A. Katus, and N. Frey Calsarcin-1 Protects Against Angiotensin-II Induced Cardiac Hypertrophy Circulation, November 27, 2007; 116(22): 2587 - 2596. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Karagulova, Y. Yue, A. Moreyra, M. Boutjdir, and I. Korichneva Protective Role of Intracellular Zinc in Myocardial Ischemia/Reperfusion Is Associated with Preservation of Protein Kinase C Isoforms J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 517 - 525. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. W. Donker, J. G. Maessen, F. Verheyen, F. C. Ramaekers, R. L. H. M. G. Spatjens, H. Kuijpers, C. Ramakers, P. M. H. Schiffers, M. A. Vos, H. J. G. M. Crijns, et al. Impact of acute and enduring volume overload on mechanotransduction and cytoskeletal integrity of canine left ventricular myocardium Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2324 - H2332. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. Cuello, S. C. Bardswell, R. S. Haworth, X. Yin, S. Lutz, T. Wieland, M. Mayr, J. C. Kentish, and M. Avkiran Protein Kinase D Selectively Targets Cardiac Troponin I and Regulates Myofilament Ca2+ Sensitivity in Ventricular Myocytes Circ. Res., March 30, 2007; 100(6): 864 - 873. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Barrientos, D. Frank, K. Kuwahara, S. Bezprozvannaya, G. C. T. Pipes, R. Bassel-Duby, J. A. Richardson, H. A. Katus, E. N. Olson, and N. Frey Two Novel Members of the ABLIM Protein Family, ABLIM-2 and -3, Associate with STARS and Directly Bind F-actin J. Biol. Chem., March 16, 2007; 282(11): 8393 - 8403. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. G. Laustsen, S. J. Russell, L. Cui, A. Entingh-Pearsall, M. Holzenberger, R. Liao, and C. R. Kahn Essential Role of Insulin and Insulin-Like Growth Factor 1 Receptor Signaling in Cardiac Development and Function Mol. Cell. Biol., March 1, 2007; 27(5): 1649 - 1664. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Moza, L. Mologni, R. Trokovic, G. Faulkner, J. Partanen, and O. Carpen Targeted Deletion of the Muscular Dystrophy Gene myotilin Does Not Perturb Muscle Structure or Function in Mice Mol. Cell. Biol., January 1, 2007; 27(1): 244 - 252. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Hoshijima Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1313 - H1325. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. M. Samarel Costameres, focal adhesions, and cardiomyocyte mechanotransduction Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2291 - H2301. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. P. Maddatu, S. M. Garvey, D. G. Schroeder, W. Zhang, S.-Y. Kim, A. I. Nicholson, C. J. Davis, and G. A. Cox Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival Hum. Mol. Genet., November 1, 2005; 14(21): 3179 - 3189. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. S. Torsoni, T. M. Marin, L. A. Velloso, and K. G. Franchini RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1488 - H1496. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. M. Guzzo, M. Salih, E. D. Moore, and B. S. Tuana Molecular properties of cardiac tail-anchored membrane protein SLMAP are consistent with structural role in arrangement of excitation-contraction coupling apparatus Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1810 - H1819. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Heineke, H. Ruetten, C. Willenbockel, S. C. Gross, M. Naguib, A. Schaefer, T. Kempf, D. Hilfiker-Kleiner, P. Caroni, T. Kraft, et al. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc PNAS, February 1, 2005; 102(5): 1655 - 1660. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Schoffstall, A. Kataoka, A. Clark, and P. B. Chase Effects of Rapamycin on Cardiac and Skeletal Muscle Contraction and Crossbridge Cycling J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 12 - 18. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. M. Miano, N. Ramanan, M. A. Georger, K. L. de Mesy Bentley, R. L. Emerson, R. O. Balza Jr., Q. Xiao, H. Weiler, D. D. Ginty, and R. P. Misra Restricted inactivation of serum response factor to the cardiovascular system PNAS, December 7, 2004; 101(49): 17132 - 17137. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. S. Walker and P. P. de Tombe Titin and the Developing Heart Circ. Res., April 16, 2004; 94(7): 860 - 862. [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2004 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |