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J Mol Cell Cardiol. 2018 Apr;117:1-18. doi: 10.1016/j.yjmcc.2018.02.012. Epub 2018 Feb 19.

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

Author information

1
Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK.
2
Institute for Experimental Medical Research, University of Oslo and Oslo University Hospital, Oslo, Norway.
3
Institute for Experimental Medical Research, University of Oslo and Oslo University Hospital, Oslo, Norway; Bjørknes College, Oslo, Norway; Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.
4
Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.
5
Heart, Lung and Vascular Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
6
Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK; Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium. Electronic address: llewelyn.roderick@kuleuven.be.

Abstract

The shortening of sarcomeres that co-ordinates the pump function of the heart is stimulated by electrically-mediated increases in [Ca2+]. 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 ETA- or ETB-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 Ca2+ transients in adult rat ventricular myocytes. The negative inotropic phase was ETB receptor-dependent, whereas the positive inotropic response and increase in peak amplitude of systolic Ca2+ transients required ETA receptor 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 (InsP3) signalling and protein kinase C epsilon (PKCε). The positive inotropic action and the enhancement in Ca2+ transient amplitude induced by ET-1 were independent of InsP3 signalling, 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 Ca2+ transients by PKCε following ET-1 stimulation. Thus, our data provide a new role and mechanism of action for InsP3 and PKCε in mediating the negative inotropic response and in restraining the positive inotropy and enhancement in Ca2+ transients following ET-1 stimulation.

KEYWORDS:

Cardiac myocyte; ECC; Endothelin; InsP(3); PKC

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