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Contractile responses to endothelin-1 are regulated by PKC phosphorylation of cardiac myosin binding protein-C in rat ventricular myocytes

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The shortening of sarcomeres that co-ordinates the pump function of the heart is stimulated by electrically-mediated increases in [Ca]. This process of excitation-contraction coupling (ECC) is subject to modulation by neurohormonal mediators that tune the output of the heart to meet the needs of the organism. Endothelin-1 (ET-1) is a potent modulator of cardiac function with effects on contraction amplitude, chronotropy and automaticity. The actions of ET-1 are evident during normal adaptive physiological responses and increased under pathophysiological conditions, such as following myocardial infarction and during heart failure, where ET-1 levels are elevated. In myocytes, ET-1 acts through ET- or ET-G protein-coupled receptors (GPCRs). Although well studied in atrial myocytes, the influence and mechanisms of action of ET-1 upon ECC in ventricular myocytes are not fully resolved. We show in rat ventricular myocytes that ET-1 elicits a biphasic effect on fractional shortening (initial transient negative and sustained positive inotropy) and increases the peak amplitude of systolic Catransients in adult rat ventricular myocytes. The negative inotropic phase was ETreceptor-dependent, whereas the positive inotropic response and increase in peak amplitude of systolic Catransients required ETreceptor engagement. Both effects of ET-1 required phospholipase C (PLC)-activity, although distinct signalling pathways downstream of PLC elicited the effects of each ET receptor. The negative inotropic response involved inositol 1,4,5-trisphosphate (InsP) signalling and protein kinase C epsilon (PKCε). The positive inotropic action and the enhancement in Catransient amplitude induced by ET-1 were independent of InsPsignalling, but suppressed by PKCε. Serine 302 in cardiac myosin binding protein-C was identified as a PKCε substrate that when phosphorylated contributed to the suppression of contraction and Catransients by PKCε following ET-1 stimulation. Thus, our data provide a new role and mechanism of action for InsPand PKCε in mediating the negative inotropic response and in restraining the positive inotropy and enhancement in Catransients following ET-1 stimulation.
Tijdschrift: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
ISSN: 0022-2828
Volume: 117
Pagina's: 1 - 18
Jaar van publicatie:2018
BOF-keylabel:ja
IOF-keylabel:ja
BOF-publication weight:2
CSS-citation score:1
Auteurs:International
Authors from:Higher Education
Toegankelijkheid:Open