Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase
Department of Molecular Cardiology, Osaka University Graduate School of Medicine. Circulation Journal
(Impact Factor: 3.94).
07/2013; 77(9). DOI: 10.1253/circj.CJ-13-0627
Cardiac-specific myosin light chain kinase (cMLCK) is the kinase predominantly responsible for the maintenance of the basal level of phosphorylation of cardiac myosin light chain 2 (MLC2), which it phosphorylates at Ser-15. This phosphorylation repels the myosin heads from the thick myosin filament and moves them toward the thin actin filament. Unlike smooth muscle cells, MLC2 phosphorylation in striated muscle cells appears to be a positive modulator of Ca(2+) sensitivity that shifts the Ca(2+)-force relationship toward the left and increases the maximal force response and thus does not initiate muscle contraction. Recent studies have revealed an increasing number of details of the biochemical, physiological, and pathophysiological characteristics of cMLCK. The combination of recent technological advances and the discovery of a novel class of biologically active nonstandard peptides will hopefully translate into the development of drugs for the treatment of heart diseases.
Available from: Emmanuelle Coque
- "In regards to the regulation of cardiac hypertrophy, a link has been established between ROCK and left ventricular remodeling after myocardial infarction (Hattori et al., 2004) while a study of hypertensive patients with left ventricular hypertrophy reveals that these patients display an increased ROCK activity (Gabrielli et al., 2014). Finally, given that MLC is a substrate of ROCK and that it controls smooth muscle contraction (reviewed by Tsukamoto and Kitakaze, 2013), it would appear evident that the RhoA/ROCK pathway plays a role in cardiac contraction. However, to our knowledge, there is yet to be a study of the impact of ROCK activation and/or inactivation on contractile properties of the heart. "
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ABSTRACT: Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.
Frontiers in Neuroscience 08/2014; 8. DOI:10.3389/fnins.2014.00271 · 3.66 Impact Factor
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ABSTRACT: The phosphorylation level of MLC-2v is decreased by I/R.•This decrease contributes to the depressed myofilament Ca2 + sensitivity after I/R.•The loss of cMLCK but not cMLCP inhibits the phosphorylation of MLC-2v during I/R.•I/R-activated MMP-2 but not calpains, caspase-3, or proteasome cleaves cMLCK.•MMP-2 inhibition also improves post-ischemic Ca2 + transients in cardiomyocytes.
Journal of Molecular and Cellular Cardiology 12/2014; 77. DOI:10.1016/j.yjmcc.2014.10.004 · 4.66 Impact Factor
Available from: James T Pearson
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ABSTRACT: Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.
07/2015; 6(7):2015-6. DOI:10.4239/wjd.v6.i7.943
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