Gß4γ1 as a modulator of M3 muscarinic receptor signalling and novel roles of Gß1 subunits in the modulation of cellular signalling.

Much is known about the how Gßγ 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 Gß and Gγ are wired into different signalling pathways. Here, using an siRNA screen for different Gß and Gγ subunits, we examined an endogenous M3 muscarinic receptor signalling pathway in HEK 293 cells. We observed that Gß(4) subunits were critical for calcium signalling and a downstream surrogate measured as ERK1/2 MAP kinase activity. A number of Gγ subunits could partner with Gß(4) but the best coupling was seen via Gß(4)γ(1). Intriguingly, knocking down Gß(1) actually increased signalling through the M3-mAChR most likely via an increase in Gß(4) levels. We noted that Gß(1) occupies the promoter of Gß(4) and may participate in maturation of its mRNA. This highlights a new role for Gßγ signalling beyond their canonical roles in cellular signalling.