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

α2-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-ARs, found in the myocellular sarcole...

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Bibliographic Details
Published in:Pharmacology & therapeutics (Oxford) 2019-05, Vol.197, p.179-190
Main Authors: Alekseev, Alexey E., Park, Sungjo, Pimenov, Oleg Yu, Reyes, Santiago, Terzic, Andre
Format: Article
Language:English
Subjects:
Animals
Ca2+ handling
Cardioprotection
Catecholamine
Cell signaling
Feedback, Physiological
G-protein coupled receptors
Heart - physiology
Heart Diseases - drug therapy
Heart Diseases - physiopathology
Heart failure
Humans
Receptors, Adrenergic, alpha-2 - physiology
Sarcolemma - physiology
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Summary:α2-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-ARs, 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 α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions in cardiac muscle. 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 pharmacological targeting of these receptors. Prospective cardiac-specific gene or cell-based therapeutic approaches aimed at repairing or improving stress-protective α2-AR signaling may offer an alternative towards enhanced preservation of cardiac muscle structure and function.
ISSN:0163-7258
1879-016X
DOI:10.1016/j.pharmthera.2019.01.007