Sarcolemmal α2-adrenoceptors in feedback control of myocardial response to sympathetic challenge

Publication date: Available online 28 January 2019Source: Pharmacology & TherapeuticsAuthor(s): Alexey E. Alekseev, Sungjo Park, Oleg Yu Pimenov, Santiago Reyes, Andre TerzicAbstractα2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back loop mechanism that moderates norepinephrine surges. We recently identified that postsynaptic α2-AR, found in the myocellular sarcolemma, also contribute to a muscle-delimited feedback control capable of attenuating mobilization of intracellular Ca2+ and myocardial contractility. This previously unrecognized cardiac muscle delimited α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions. Specifically, in ventricular myocytes, nitric oxide (NO) and cGMP are the intracellular messengers of α2-AR signal transduction pathways that gauge the kinase-phosphatase balance and manage cellular Ca2+ handling preventing catecholamine-induced Ca2+ overload. Moreover, α2-AR signaling counterbalances phospholipase C – PKC-dependent mechanisms underscoring a broader cardioprotective potential under sympathoadrenergic and angiotensinergic challenge. Recruitment of such tissue-specific features of α2-AR under sustained sympathoadrenergic drive may, in principle, be harnessed to mitigate or prevent cardiac malfunction. However, cardiovascular disease may compromise peripheral α2-AR signaling limiting pharmacologica...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research