Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Peter Chidiac

2nd Supervisor

Dr. Brad Urquhart

Co-Supervisor

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 Gai-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 Gai-dependent signalling while promoting Gbg-dependent signalling in Gi-coupled GPCRs.

GPSM3 significantly inhibited b-arrestin recruitment to α2A-adrenergic and m-opioid receptors via a Gbg-dependent mechanism,with no effect to Gs- and Gq/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 α2A-adrenergic and m-opioid receptors.

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

Available for download on Friday, August 21, 2020

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