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

Alexey E. Alekseev, Sungjo Park, Oleg Yu Pimenov, Santiago Reyes, Andre Terzic

Research output: Contribution to journalReview article

1 Citation (Scopus)

Abstract

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 Ca 2+ 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 Ca 2+ handling preventing catecholamine-induced Ca 2+ 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.

Original languageEnglish (US)
JournalPharmacology and Therapeutics
DOIs
StatePublished - Jan 1 2019

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Adrenergic Receptors
Myocardium
Adrenergic Neurons
Sarcolemma
Type C Phospholipases
Phosphoric Monoester Hydrolases
Synapses
Muscle Cells
Catecholamines
Signal Transduction
Norepinephrine
Nitric Oxide
Protein Isoforms
Cardiovascular Diseases
Phosphotransferases
Central Nervous System
Pharmacology
Muscles
Genes

Keywords

  • Ca handling
  • Cardioprotection
  • Catecholamine
  • Cell signaling
  • G-protein coupled receptors
  • Heart failure

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Sarcolemmal α2-adrenoceptors in feedback control of myocardial response to sympathetic challenge. / Alekseev, Alexey E.; Park, Sungjo; Pimenov, Oleg Yu; Reyes, Santiago; Terzic, Andre.

In: Pharmacology and Therapeutics, 01.01.2019.

Research output: Contribution to journalReview article

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