Abstract
Every animal species expresses hundreds of different G protein-coupled receptors (GPCRs) that respond to a wide variety of external stimuli. GPCRs-driven signaling pathways are involved in pretty much every physiological function and in many pathologies. Therefore, GPCRs are targeted by about a third of clinically used drugs. The signaling of most GPCRs via G proteins is terminated by the phosphorylation of active receptor by specific kinases (GPCR kinases, or GRKs) and subsequent binding of arrestin proteins, that selectively recognize active phosphorylated receptors. In addition, GRKs and arrestins play a role in multiple signaling pathways in the cell, both GPCR-initiated and receptor-independent. Here we focus on the mechanisms of GRK- and arrestin-mediated regulation of GPCR signaling, which includes homologous desensitization and redirection of signaling to additional pathways by bound arrestins.
Highlights
Reviewed by: Federico Mayor, Autonomous University of Madrid, Spain Philippe Rondard, Centre National de la Recherche Scientifique (CNRS), France
The signaling of most G protein-coupled receptors (GPCRs) via G proteins is terminated by the phosphorylation of active receptor by specific kinases (GPCR kinases, or GRKs) and subsequent binding of arrestin proteins, that selectively recognize active phosphorylated receptors
Class C GPCRs are dimers, consisting of two 7TM units, with ligand-binding pocket localized on a separate extracellular Venus flytrap domain homologous to bacterial proteins involved in transporting amino acids and ions (Fredriksson et al, 2003; Pin and Bettler, 2016)
Summary
G protein-coupled receptors are the largest family of signaling proteins. Structurally, the cores of all GPCRs are very similar: extracellular N-terminus, seven membrane-spanning α-helices (TM), and intracellular C-terminus, with variable extracellular and intracellular elements (Bockaert and Pin, 1999; Fredriksson et al, 2003). These receptors have large N-termini, which contain the high-affinity part of the ligand-binding site, with the pocket between helices constituting the lower affinity part. Class C GPCRs are dimers, consisting of two 7TM units, with ligand-binding pocket localized on a separate extracellular Venus flytrap domain homologous to bacterial proteins involved in transporting amino acids and ions (Fredriksson et al, 2003; Pin and Bettler, 2016). In class C GPCRs many allosteric modulators bind to the pocket between helices in the 7TM part, so that after the deletion of the extracellular elements the remaining heptahelical domain functions pretty much like a class A receptor binding allosteric regulators as ligands (Goudet et al, 2004). In case of GPCRs, rapid signal turnoff is accomplished by a conserved two-step mechanism: receptor phosphorylation by GRKs followed by arrestin binding (Carman and Benovic, 1998)
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