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

Abstract

Enhanced signaling in myocytes by the G protein Gq has been implicated in cardiac hypertrophy and the transition to heart failure. alpha1-Adrenergic receptors (alpha1-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 alpha1-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 alpha 1A and alpha 1B 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 alpha1-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 alpha1-AR antagonists in the treatment of hypertension and symptomatic prostate enlargement.

Figure 1. Mechanisms of 7-TM receptor diversification.

The classic paradigm is shown in A, where a receptor (denoted “R,” “R1,” or “R2”) couples to a G protein (denoted “G”), which activates an effector (denoted “E”). In B, 1 receptor couples to 2 G proteins, thereby activating 2 effectors. In C, receptor coupling to 2 G proteins modulates a single effector. Scenario D involves coupling to a single G protein, but the α and βγ subunits carry out distinct signaling to 2 different effectors. In E, feedback modulation of the receptor (such as phosphorylation) by 1 effector (or an effector-activated event such as protein kinase activation) causes the receptor to couple to the second G protein. In F, the functional coupling of R₁ to the G protein is altered by its heterodimerization with another receptor, R₂. In contrast to the above, 7-TM receptors can couple directly to effectors without the G protein intermediary (G). In H and I, the 7-TM receptor is affected by, or acts upon, other types of receptors (denoted “r”), such as receptor tyrosine kinases, which alter signaling via the respective cognate pathways. In J, a signaling moiety (SM) is redistributed to a microdomain by the scaffolding action of the arrestins. These proteins act both to partially desensitize the receptor and to evoke a second effector signal by this scaffolding. One or more of these mechanisms may be responsible for the specialized signaling of the α₁-AR required for normal hypertrophy, as elucidated by O’Connell et al. (8).