RGS Redundancy and Implications in GPCR-GIRK Signaling

Abstract

Regulators of G protein signaling (RGS proteins) are key components of GPCR complexes, interacting directly with G protein α-subunits to enhance their intrinsic GTPase activity. The functional consequence is an accelerated termination of G protein effectors including certain ion channels. RGS proteins have a profound impact on the membrane-delimited gating behavior of G-protein-activated inwardly rectifying K(+) (GIRK) channels as demonstrated in reconstitution assays and recent RGS knockout mice studies. Akin to GPCRs and G protein αβγ subunits, multiple RGS isoforms are expressed within single GIRK-expressing neurons, suggesting functional redundancy and/or specificity in GPCR-GIRK channel signaling. The extent and impact of RGS redundancy in neuronal GPCR-GIRK channel signaling is currently not fully appreciated; however, recent studies from RGS knockout mice are providing important new clues on the impact of individual endogenous RGS proteins and the extent of RGS functional redundancy. Incorporating "tools" such as engineered RGS-resistant Gαi/o subunits provide an important assessment method for determining the impact of all endogenous RGS proteins on a given GPCR response and an accounting benchmark to assess the impact of individual RGS knockouts on overall RGS redundancy within a given neuron. Elucidating the degree of regulation attributable to specific RGS proteins in GIRK channel function will aid in the assessment of individual RGS proteins as viable therapeutic targets in epilepsy, ataxia's, memory disorders, and a growing list of neurological disorders.

Keywords: Epilepsy; Functional redundancy; G-protein-activated inward rectifier K(+) channel; G-protein-coupled receptor; GTPase-activating protein; Neuronal excitability; Regulators of G protein signaling; “Slow” excitatory synaptic transmission; “Slow” inhibitory synaptic transmission.