Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify

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Abstract
Enhanced signaling in myocytes by the G protein Gq has been implicated in cardiac hypertrophy and the transition to heart failure. α1-Adrenergic receptors (α1-ARs) are members of the 7-transmembrane-spanning domain (7-TM) receptor family and signal via interaction with Gq in the heart. The specific effects of a loss of α1-AR signaling in the heart are explored by O’Connell et al. in this issue of the JCI (see the related article beginning on page 1005). Paradoxically, gene ablation of the α1A and α1B subtypes in mice results in a maladaptive form of reactive cardiac hypertrophy from pressure overload, with a predisposition to heart failure. Thus signaling to the α1-AR (compared with signaling from other receptors such as angiotensin receptors, which also couple to Gq) appears to be specifically required for a normal hypertrophic response. This represents another example of how receptors that share common G proteins have diversified, developing unique signaling programs. These findings may have particular clinical relevance because of the widespread use of α1-AR antagonists in the treatment of hypertension and symptomatic prostate enlargement.