Regulation of G-Protein-Coupled Receptor Signalling by the Scaffolding Proteins Spinophilin/Neurabin 2 and Neurabin 1

Denis      Sarrouilhe; Thierry      Metaye

Abstract

Neurabin 1 and neurabin 2/spinophilin were discovered in late 1990s on the basis of their F-actin-binding and protein phosphatase 1 catalytic subunit (PP1c) modulation activities. The neurabins are proteins with modular domains, such as one F-actin-, a receptor- (not found in neurabin 1) and a PP1c-binding domains, a PSD95/DLG/zo-1, three coiledcoil domains and a sterile alpha motif (not found in spinophilin) that govern protein-protein interactions. In the past years, the roles of neurabins have evolved from PP1c-regulatory subunits to important scaffolds binding to a rapidly growing list of cellular proteins. Among the spinophilin and neurabin 1 interactomes, some partner proteins are involved in G-proteincoupled receptor (GPCR) signalling. The most significant difference is that spinophilin, but not neurabin 1, interacts with and plays a specific and direct role in the regulation of at least the α-adrenergic (AR), muscarinic-acetylcholine (m- AChR), dopamine D2 and mu opioid receptors. In contrast, the two scaffolding proteins bind to different members of the regulator of G-protein signalling (RGS) familly. Spinophilin antagonizes multiple functions of arrestin and G-proteincoupled receptor kinase 2 in α-AR signalling. Moreover, spinophilin and neurabin 1 form a functional pair of opposing regulators that reciprocally regulate signalling intensity by the α1-AR. To date, the data on the regulation of GPCR signalling by neurabin 1 are very sparse and the reciprocal regulation seems not to be a general phenomenon. Several studies make on the α1-AR and the m-AChR suggest that spinophilin may selectively regulate Gq-coupled receptor signalling. This review highlights information regarding spinophilin and neurabin 1 function in GPCR signalling.

Keywords: GPCR, G protein, neurabin, protein phosphatase 1, RGS protein, scaffold protein, spinophilin, F-actin-binding domain, cAMP-dependent PK, PP1c-binding domain, sterile alpha motif, F-actin, G-PROTEIN-COUPLED RECEPTOR SIGNALLING, Xenopus laevis