Abstract
Transient Receptor Potential Canonical 4 (TRPC4) forms non-selective cation channels implicated in the regulation of diverse physiological functions, including smooth muscle contractility, synaptic transmission, and neurodegeneration. Unique among TRPC subfamily members, TRPC4 activation is dependent on Gi/o subgroup of heterotrimeric G proteins in addition to stimulation of phospholipase C pathway. Previously, the Gi/o, rather than Gbetgamma, subunits were suggested to mediate Gi/o-induced TRPC4 activation. Because the lifetime and availability of Galpha-GTP are regulated by Regulators of G protein signaling (RGS) and GoLoco domain-containing proteins via their GTPase-activating protein (GAP) and guanosine nucleotide dissociation inhibition (GDI) functions, respectively, we tested how RGS and GoLoco domain proteins affect TRPC4 currents activated via Gi/o-coupled receptors. Using whole-cell patch clamp recordings, we show that both RGS (RGS4, RGS6, RGS12, or RGS14) and GoLoco domain proteins (LGN, AGS3, RGS12, or RGS14) suppress receptor-mediated TRPC4 activation without eliciting any basal current. The inhibitory effects are dependent on the GAP and GoLoco domains and facilitated by enhancing membrane targeting of the GoLoco domains of AGS3. In addition, the Gi/o-specific RGS proteins, but not the GoLoco domain proteins, accelerate desensitization of receptor activation-evoked TRPC4 currents. We found that the inhibitory effects of RGS and GoLoco domains are additive and are most prominent with RGS proteins that contain both the RGS and GoLoco domains, i.e. RGS12 and RGS14. Our data support the notion that the Galpha, but not Gbetagamma, arm of the Gi/o signaling is involved in TRPC4 activation and indicate that acting through Gi/o via GAP and GDI functions, RGS and GoLoco domain proteins can fine tune TRPC4 activity and thereby allow delicate regulation of cellular functions in nervous and other systems.
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