Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Using saponin skinned fibers, we investigated whether decreased myofilament calcium responsiveness and contractile activation may in part contribute to heart failure in an animal model of idiopathic spontaneous cardiomyopathy (SCM). We addressed the question as to whether there are adaptive changes at the level of the thin myofilaments in turkey poults with SCM. The calcium concentration ([Ca2+]) required for 50% activation ([Ca2+]50%) was 0.80 +/- 0.12 microM (n = 12) vs. 0.76 +/- 0.08 microM (n = 12) and the Hill coefficient was 1.98 +/- 0.20 (n = 12) vs. 2.14 +/- 0.38 (n = 12) for control and SCM muscles respectively. Maximal Ca(2+)-activated force was not different between control fibers and fibers from failing hearts (3.83 +/- 0.88 g/mm2 vs. 3.65 +/- 0.39 g/mm2). These data indicate there are no differences in calcium-activation between fibers from control and failing myocardium. The effects of caffeine, an agent that increases myofilament Ca2+ sensitivity, were also studied. Addition of 10 mM caffeine resulted in a 0.06 pCa unit leftward shift of the force-pCa relationship in control hearts and 0.14 pCa units in SCM hearts. Caffeine (30 mM) increased force by 26 +/- 2.1% (n = 7) in control fibers and 44.5 +/- 8.7% (n = 8) in myopathic fibers at a pCa of 6.0. The increased responsiveness of muscles from failing hearts to caffeine indicates adaptive changes at the level of the thin myofilaments. Addition of dibutyryl-3',5'-cyclic-Adenosine Monophosphate (D-cAMP) resulted in a 0.21 pCa rightward shift on the calcium axis to higher intracellular calcium concentrations in control myocardium and 0.38 pCa units in SCM failing myocardium. The muscles were also sinusoidally oscillated at frequencies ranging between 0.01 and 100 Hz. In this analysis the frequency at which dynamic stiffness is minimum is taken as a measure of cross-bridge cycling rate. In control muscles, the frequency of minimum stiffness (fmin) was 1.20 +/- 0.11 (n = 4) whereas it was 0.71 +/- 0.08 Hz (n = 4) in myopathic muscles. The addition of 10 microM D-cAMP shifted fmin from 1.20 +/- 0.11 Hz to 1.68 +/- 0.09 Hz (delta = 0.48 +/- 0.06) in control fibers whereas in SCM fibers it caused greater shift of fmin from 0.71 +/- 0.08 Hz to 1.73 +/- 0.08 Hz (delta = 1.02 +/- 0.07). This differential effect of D-cAMP indicates adaptive changes at the level of the myofilaments.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1992 Dec
PMID:Calcium-activated force in a turkey model of spontaneous dilated cardiomyopathy: adaptive changes in thin myofilament Ca2+ regulation with resultant implications on contractile performance. 133 13

In the present work we have modeled the Michaelis complex of the cyclic-Adenosine Monophosphate Dependent (cAMD) Protein Kinase A (PKA) with Mg(2)ATP and the heptapeptide substrate Kemptide by classical molecular dynamics. The chosen synthetic substrate is relevant for its high efficiency and small size, and it has not been used in previous theoretical studies. The structural analysis of the data generated along the 6 ns simulation indicates that the modeled substrate-enzyme complex mimics the substrate binding pattern known for PKA. The values of the average prereactive distances obtained from the simulation do not exclude any of the two limiting situations proposed as mechanisms in the literature for the phosphorylation reaction (dissociative and associative) because the system oscillates between configurations compatible with each of them. Furthermore, the results obtained for the average interaction distances between active site residues concord in suggesting the plausibility of an alternative third reaction mechanism.
J Comput Aided Mol Des
PMID:Comparative study of the prereactive protein kinase A Michaelis complex with kemptide substrate. 1800 70

The cardiac voltage-gated Na(+) channel, Na(V)1.5, is responsible for the upstroke of the action potential in cardiomyocytes and for efficient propagation of the electrical impulse in the myocardium. Even subtle alterations of Na(V)1.5 function, as caused by mutations in its gene SCN5A, may lead to many different arrhythmic phenotypes in carrier patients. In addition, acquired malfunctions of Na(V)1.5 that are secondary to cardiac disorders such as heart failure and cardiomyopathies, may also play significant roles in arrhythmogenesis. While it is clear that the regulation of Na(V)1.5 protein expression and function tightly depends on genetic mechanisms, recent studies have demonstrated that Na(V)1.5 is the target of various post-translational modifications that are pivotal not only in physiological conditions, but also in disease. In this review, we examine the recent literature demonstrating glycosylation, phosphorylation by Protein Kinases A and C, Ca(2+)/Calmodulin-dependent protein Kinase II, Phosphatidylinositol 3-Kinase, Serum- and Glucocorticoid-inducible Kinases, Fyn and Adenosine Monophosphate-activated Protein Kinase, methylation, acetylation, redox modifications, and ubiquitylation of Na(V)1.5. Modern and sensitive mass spectrometry approaches, applied directly to channel proteins that were purified from native cardiac tissues, have enabled the determination of the precise location of post-translational modification sites, thus providing essential information for understanding the mechanistic details of these regulations. The current challenge is first, to understand the roles of these modifications on the expression and the function of Na(V)1.5, and second, to further identify other chemical modifications. It is postulated that the diversity of phenotypes observed with Na(V)1.5-dependent disorders may partially arise from the complex post-translational modifications of channel protein components.
J Mol Cell Cardiol 2015 May
PMID:Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications. 2574 40