Article

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: 3.69). 07/2013; 77(9). DOI: 10.1253/circj.CJ-13-0627
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
51 Views
  • [Show abstract] [Hide abstract]
    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 · 5.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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