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 language | English (US) |
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Pages (from-to) | 1092-1100 |
Number of pages | 9 |
Journal | Circulation research |
Volume | 85 |
Issue number | 11 |
DOIs | |
State | Published - Nov 26 1999 |
Externally published | Yes |
Keywords
- CAMP compartmentalization
- G protein
- Heart failure
- β-adrenergic receptor subtype
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine