Recent advances in cardiac β2-adrenergic signal transduction

R. P. Xiao, H. Cheng, Y. Y. Zhou, M. Kuschel, E. G. Lakatta

Research output: Contribution to journalReview article

Abstract

Recent studies have added complexities to the conceptual framework of cardiac β-adrenergic receptor (β-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for β1-AR stimulation, the β2-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), β2-AR couples to pertussis toxin-sensitive G(i) proteins, G(i)2 and G(i)3. The coupling of β2-AR to G(i) proteins mediates, to a large extent, the differential actions of the β-AR subtypes on cardiac Ca2+ handling, contractility, cAMP accumulation, and PKA- mediated protein phosphorylation. The extent of G(i) coupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in β2-AR-mediated cardiac responses. There is an apparent dissociation of β2-AR-induced augmentations of the intracellular Ca2+ (Ca(i)) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by G(i)- dependent functional compartmentalization of the β2-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during β- AR subtype stimulation. Emerging evidence also points to distinctly different roles of these β-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of β-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of β-AR subtypes in healthy and diseased hearts.

Original languageEnglish (US)
Pages (from-to)1092-1100
Number of pages9
JournalCirculation research
Volume85
Issue number11
DOIs
StatePublished - Nov 26 1999
Externally publishedYes

Keywords

  • CAMP compartmentalization
  • G protein
  • Heart failure
  • β-adrenergic receptor subtype

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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