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).