Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives

Recent advancements in the study of orphan G protein-coupled receptors (oGPCRs) have revealed a large number with high levels of constitutive G protein signaling. Structural studies have suggested a new paradigm in which many constitutively active oGPCRs are auto-activated by their own intrinsic protein motifs, which act as auto-agonists. This includes extracellular loop 2 acting as auto-agonist to promote active-state conformations and G protein signaling. In some cases, the oGPCRs lack inhibitory microswitches that may drive a high level of constitutive activity. In this brief review, we discuss oGPCR constitutive activity, highlighting the auto-activating orphan receptors and overview structural underpinnings of constitutive activity. A discussion into the pharmacological and cell signaling implications of oGPCR constitutive activity is provided. We also propose a new concept in which orphan GPCR constitutive activity sets the baseline tone for cellular signaling and allows for dynamic regulation of cAMP signaling. Taken together, recent mechanistic studies with many oGPCRs indicate high constitutive activity is a common phenomenon that modulates cellular signaling and that can be tuned with pharmacology. SIGNIFICANCE STATEMENT: Recent literature describes a subset of orphan Class A G protein-coupled receptors with high constitutive signaling that auto-activate by their own intrinsic protein motifs. Herein, a new concept is proposed in which oGPCR constitutive activity allows dynamic regulation of cAMP signaling. Recently solved structures and functional studies of constitutively active oGPCRs provide fresh insights into oGPCR signaling with relevance for both health and disease.