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Heterotrimeric G protein–coupled receptors (GPCRs) are found on the surface of all cells of multicellular organisms and are major mediators of intercellular communication. More than 800 distinct GPCRs are present in the human genome, and individual receptor subtypes respond to hormones, neurotransmitters, chemokines, odorants, or tastants. GPCRs represent the most widely targeted pharmacological protein class. Because drugs that target GPCRs often engage receptor regulatory mechanisms that limit drug effectiveness, particularly in chronic treatment, there is great interest in understanding how GPCRs are regulated, as a basis for designing therapeutic drugs that evade this regulation. The major GPCR regulatory pathway involves phosphorylation of activated receptors by G protein–coupled receptor kinases (GRKs), followed by binding of arrestin proteins, which prevent receptors from activating …