mRNA cargo no longer on time

Hein, Stefan; Kostin, Sawa; Schaper, Jutta

doi:10.1152/ajpheart.91528.2007

Cited by 3 publications

(2 citation statements)

References 19 publications

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“…Several studies have previously shown that Nav1.5 channels are delivered to their final destination on the membrane through the microtubule network 19, 35. Although microtubule network density was increased in TAC cardiomyocytes, the observed increased detyrosinated tubulin (ie, Glu‐tubulin) levels indicate that the microtubule network is less dynamic25 and, thus, potentially less efficient 36, 37, 38. It is, therefore, reasonable to speculate that the increased Glu‐tubulin observed in our experiments is associated with impaired Nav1.5 delivery at any subcellular location.…”

Section: Discussionmentioning

confidence: 99%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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BackgroundCardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region‐specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure.Methods and ResultsMice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham–operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole‐cell sodium current (INa) density was decreased by 30% in TAC versus sham–operated on cardiomyocytes. On macropatch analysis, INa in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter‐]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z‐groove ratios). Using scanning ion conductance microscopy, cell‐attached recordings in LM subdomains revealed decreased INa and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α‐tubulin and Glu‐tubulin expression). Superresolution microscopy showed reduced average NaV1.5 cluster size at the LM of TAC cells, in line with reduced INa.ConclusionsHeart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in NaV1.5 clustering and INa within distinct subcellular microdomains of failing cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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“…Given the major microtubule-based abnormalities of contractile and transport function in maladaptive hypertrophy, these findings constitute a second important mechanism for phosphatase-dependent pathology in the hypertrophied and failing heart. Pathological cardiac hypertrophy may be accompanied by increased density and MAP4 2 decoration of the cardiomyocyte microtubule network (1,2), which causes defects in cellular contractile (3,4) and transport (5,6) function. We recently have described, in pathological but not physiological cardiac hypertrophy, site-specific dephosphorylation of three MAP4 serine residues (7); one site is in the MAP4 projection domain, and two are in the microtubule-binding domain.…”

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confidence: 99%

Basis for MAP4 Dephosphorylation-related Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Cheng

Takahashi

Shunmugavel

et al. 2010

Journal of Biological Chemistry

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Increased activity of Ser/Thr protein phosphatases types 1 (PP1) and 2A (PP2A) during maladaptive cardiac hypertrophy contributes to cardiac dysfunction and eventual failure, partly through effects on calcium metabolism. A second maladaptive feature of pressure overload cardiac hypertrophy that instead leads to heart failure by interfering with cardiac contraction and intracellular transport is a dense microtubule network stabilized by decoration with microtubule-associated protein 4 (MAP4). In an earlier study we showed that the major determinant of MAP4-microtubule affinity, and thus microtubule network density and stability, is site-specific MAP4 dephosphorylation at Ser-924 and to a lesser extent at Ser-1056; this was found to be prominent in hypertrophied myocardium. Therefore, in seeking the etiology of this MAP4 dephosphorylation, we looked here at PP2A and PP1, as well as the upstream p21-activated kinase 1, in maladaptive pressure overload cardiac hypertrophy. The activity of each was increased persistently during maladaptive hypertrophy, and overexpression of PP2A or PP1 in normal hearts reproduced both the microtubule network phenotype and the dephosphorylation of MAP4 Ser-924 and Ser-1056 seen in hypertrophy. Given the major microtubule-based abnormalities of contractile and transport function in maladaptive hypertrophy, these findings constitute a second important mechanism for phosphatase-dependent pathology in the hypertrophied and failing heart. Pathological cardiac hypertrophy may be accompanied by increased density and MAP4 2 decoration of the cardiomyocyte microtubule network (1, 2), which causes defects in cellular contractile (3, 4) and transport (5, 6) function. We recently have described, in pathological but not physiological cardiac hypertrophy, site-specific dephosphorylation of three MAP4 serine residues (7); one site is in the MAP4 projection domain, and two are in the microtubule-binding domain. Of these, the striking dephosphorylation at feline MAP4 Ser-924 corresponding to human MAP4 Ser-914 within the first of the four KXGS repeats of the MAP4 microtubule-binding domain was especially interesting, because adenoviral expression of a dephosphomimetic Ser-924 3 Ala feline MAP4 mutant in normal cardiomyocytes phenocopied the features of microtubule network densification, stabilization, and MAP4 overdecoration seen in pathological cardiac hypertrophy. Conversely, adenoviral expression of a phosphomimetic Ser-924 3 Asp feline MAP4 mutant in normal cells caused microtubule depolymerization.This first MAP4 microtubule-binding domain KXGS motif repeat is closely homologous to the corresponding first repeat in the neuronal MAP Tau, with feline MAP4 Ser-924 corresponding to human full-length Tau Ser-262, and it is known that phosphorylation of both MAP4 and Tau at the respective serine residues virtually abolishes MAP binding to microtubules, with consequent microtubule network destabilization (8, 9). Indeed, hyperphosphorylation of Tau Ser-262, leading to aggregation of the detached Tau into...

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Site-specific Microtubule-associated Protein 4 Dephosphorylation Causes Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Panneerselvam

Samanna

Cheng

et al. 2010

Journal of Biological Chemistry

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In severe pressure overload-induced cardiac hypertrophy, a dense, stabilized microtubule network forms that interferes with cardiocyte contraction and microtubule-based transport. This is associated with persistent transcriptional up-regulation of cardiac ␣-and ␤-tubulin and microtubule-stabilizing microtubule-associated protein 4 (MAP4). There is also extensive microtubule decoration by MAP4, suggesting greater MAP4 affinity for microtubules. Because the major determinant of this affinity is site-specific MAP4 dephosphorylation, we characterized this in hypertrophied myocardium and then assessed the functional significance of each dephosphorylation site found by mimicking it in normal cardiocytes. We first isolated MAP4 from normal and pressure overload-hypertrophied feline myocardium; volume-overloaded myocardium, which has an equal degree and duration of hypertrophy but normal functional and cytoskeletal properties, served as a control for any nonspecific growth-related effects. After cloning cDNA-encoding feline MAP4 and obtaining its deduced amino acid sequence, we characterized by mass spectrometry any site-specific MAP4 dephosphorylation. Solely in pressure overload-hypertrophied myocardium, we identified striking MAP4 dephosphorylation at Ser-472 in the MAP4 N-terminal projection domain and at Ser-924 and Ser-1056 in the assembly-promoting region of the C-terminal microtubule-binding domain. Site-directed mutagenesis of MAP4 cDNA was then used to switch each serine to non-phosphorylatable alanine. Wild-type and mutated cDNAs were used to construct adenoviruses; microtubule network density, stability, and MAP4 decoration were assessed in normal cardiocytes following an equivalent level of MAP4 expression. The Ser-924 3 Ala MAP4 mutant produced a microtubule phenotype indistinguishable from that seen in pressure overload hypertrophy, such that Ser-924 MAP4 dephosphorylation during pressure overload hypertrophy may be central to this cytoskeletal abnormality.Although many important alterations have been described in the properties of hypertrophied myocardium, the mechanisms responsible for contractile dysfunction and many other maladaptive changes of cardiac muscle cells, or cardiocytes, have yet to be fully defined. Although most research in this area has focused on structural and regulatory changes within the myofilament, it has also been found that changes in the microtubule component of the extra-myofilament cytoskeleton may lead both to contractile dysfunction by increasing the internal resistance to sarcomere motion (1, 2) and to disordered cellular homeostasis by impeding cytoskeleton-based intracellular transport (3-6).Our major original finding was that, in severe pressure overload cardiac hypertrophy with increased ventricular wall stress, there is the early appearance and then the persistence of a dense microtubule network and associated contractile dysfunction (7,8). We have now found several synergistic bases for this dense microtubule network. First, during hypertrophy there is persistent tran...

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mRNA cargo no longer on time

Cited by 3 publications

References 19 publications

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Basis for MAP4 Dephosphorylation-related Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Site-specific Microtubule-associated Protein 4 Dephosphorylation Causes Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

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