Recent advances in cardiac beta(2)-adrenergic signal transduction

Circ Res. 1999 Nov 26;85(11):1092-100. doi: 10.1161/01.res.85.11.1092.


Recent studies have added complexities to the conceptual framework of cardiac beta-adrenergic receptor (beta-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for beta(1)-AR stimulation, the beta(2)-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), beta(2)-AR couples to pertussis toxin-sensitive G(i) proteins, G(i2) and G(i3). The coupling of beta(2)-AR to G(i) proteins mediates, to a large extent, the differential actions of the beta-AR subtypes on cardiac Ca(2+) 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 beta(2)-AR-mediated cardiac responses. There is an apparent dissociation of beta(2)-AR-induced augmentations of the intracellular Ca(2+) (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 beta(2)-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during beta-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these beta-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of beta-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of beta-AR subtypes in healthy and diseased hearts.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Calcium / physiology
  • Cyclic AMP / physiology
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Dogs
  • GTP-Binding Proteins / physiology
  • Heart / drug effects
  • Heart / physiology*
  • Heart Failure / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Mice, Transgenic
  • Muscle Proteins / drug effects
  • Muscle Proteins / physiology*
  • Myocardial Contraction / drug effects
  • Myocardial Contraction / physiology*
  • Myocardium / metabolism*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Rats
  • Receptors, Adrenergic, beta-1 / drug effects
  • Receptors, Adrenergic, beta-1 / physiology
  • Receptors, Adrenergic, beta-2 / classification
  • Receptors, Adrenergic, beta-2 / drug effects
  • Receptors, Adrenergic, beta-2 / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Species Specificity


  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Muscle Proteins
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Proteins
  • Calcium