Gβ4γ1 as a modulator of M3 muscarinic receptor signalling and novel roles of Gβ1 subunits in the modulation of cellular signalling

Much is known about the how G beta gamma subunits regulate effectors in response to G protein-coupled receptor stimulation. However, there is still a lot we don't know about how specific combinations of G beta and G gamma are wired into different signalling pathways. Here, using an siRNA screen for different G beta and G gamma subunits, we examined an endogenous M3 muscarinic receptor signalling pathway in HEK 293 cells. We observed that G beta(4) subunits were critical for calcium signalling and a downstream surrogate measured as ERK1/2 MAP kinase activity. A number of G gamma subunits could partner with G beta(4) but the best coupling was seen via G beta(4)gamma(1). Intriguingly, knocking down G beta(1) actually increased signalling through the M3-mAChR most likely via an increase in G beta(4) levels. We noted that G beta(1) occupies the promoter of G beta(4) and may participate in maturation of its mRNA. This highlights a new role for G beta gamma signalling beyond their canonical roles in cellular signalling. (C) 2015 Elsevier Inc. All rights reserved