Effects of G Protein Signalling Modulator 3 on Cellular Signalling

Aneta A. Surmanski, The University of Western Ontario

Abstract

G protein coupled receptors (GPCRs) promote G protein heterotrimer (Gα·GDP/Gbg) activation.GPCRsignalling is limited via G protein GTPase activity and b-arrestin-receptor interactions. G Protein Signalling Modulators (GPSMs) are proteins that may influence receptor signalling through G protein activity. GPSM3 modulates their activity by binding to Ga_i-GDP, limiting nucleotide exchange and preventing its re-association to Gbg. The impact of GPSM3 on signalling is unknown.We hypothesize that GPSM3 will decrease Ga_i-dependent signalling while promoting Gbg-dependent signalling in G_i-coupled GPCRs.

GPSM3 significantly inhibited b-arrestin recruitment to α_2A-adrenergic and m-opioid receptors via a Gbg-dependent mechanism,with no effect to G_s- and G_q/11-coupled GPCRs. N-terminal truncation and single point mutations in three distinct regions of GPSM3 decreased the inhibitory effect of GPSM3 on b-arrestin recruitment to α_2A-adrenergic and m-opioid receptors.

Thus, our data suggest that GPSM3 negatively regulates b-arrestin-G_i-coupled GPCRinteractions, which could serve as a potential therapeutic target for future pharmaceuticals.