Physiological control of temporal behavior of RGS protein by the reciprocal regulation by PI(3,4,5)P₃ and Ca²⁺/calmodulin

Abstract

'Regulators of G-protein-signalling (RGS)' are a family of proteins, which accelerate intrinsic GTP-hydrolysis on α subunits of trimeric G-proteins and play crucial roles in the physiological regulation of G-protein mediated cell signaling. If RGS proteins were active unrestrictedly, it would completely suppress various G protein-mediated signallings as has been seen in the over-expression experiments of RGS proteins. Therefore, it is quite important to understand how the actions of RGS proteins are regulated in the physiological conditions. We recently revealed in cardiac myocytes a physiological control of RGS proteins. The voltage-dependent formation of Ca²⁺/calmodulin (CaM) facilitated the GTPase-activity of RGS protein via removing intrinsic inhibition mediated by a kind of phospholipid, phosphatidylinositol-3,4,5,-trisphosphate (PI(3,4,5)P₃). This modulation of RGS-action underlies a temporal behavior of G-protein-gated K⁺ (K_G) channels, called 'relaxation',. Further examination using protein-lipid co-sedimentation assay, we detected the specific interaction between RGS4 and PI(3,4,5)P₃ (but not other PIPs), which was decreased by Ca²⁺/CaM. The allosteric modulation is exclusively performed within RGS domain. We identified the clusters of positively charged residues in RGS domain as a candidate of the molecular switch of PI(3,4,5)P₃/CaM-modulation. Because the residues are conserved in almost all RGS protein subtypes, the allosteric modulation of RGS proteins should be important in the physiological control of G-protein signaling by various RGS proteins. [Jpn J Physiol 54 Suppl:S66 (2004)]