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

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 ET_A- or ET_B-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 ET_B receptor-dependent, whereas the positive inotropic response and increase in peak amplitude of systolic Ca²⁺ transients required ET_A 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 The positive inotropic action and the enhancement in Ca²⁺ transient amplitude induced by ET-1 were independent of InsP₃ signalling, but suppressed by Serine 302 in cardiac myosin binding protein-C was identified as a substrate that when phosphorylated contributed to the suppression of contraction and Ca²⁺ transients by duanyu1531ε following ET-1 stimulation. Thus, our data provide a new role and mechanism of action for InsP₃ and duanyu1531ε in mediating the negative inotropic response and in restraining the positive inotropy and enhancement in Ca²⁺ transients following ET-1 stimulation.

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