The n terminal domain of RGS4 confers regulatory specificity in g protein-receptor signaling

KGS proteii accelerate GTP hydrolysis by G alpha subunits. thereby in attivaiing signaling. RGS-1 ia a GTPase activating protein (GAP) for Giami Gq class alpha subunits and inhibits signaling via these G proteins in vivo. p used Gq class knockout mice to evaluate the potency and selectivity ot KGS-1 in modulating Ca2 + signaling transduced by different coupled re ccptors. Interestingly. RGS4 inhibited PLG activity ami Ga2+ signaling in ,1 receptor elective manner in both permeabilized cells and cells dialyed u it h 1KJS-1 hrougli a patch pipette. The respoiiae of mouse pancreatic acinar cells tu carbacliol was about I and M fold more sensitive to RCIS-1 than that of bombehin and GCK in wiUitype and Gq rlas knockout mice. Tim-,. Gq aliha Mibunit- couple these receptors promiscuously. Regulatory specilicilv coiiferrd by R(iS-l interaction with the receptor complex. The N terminal do main of KGS-1 confers high apparent affinity binding and is the key discriminator ot receptor signaling complexes coupled via Gq. In intact cells, ihe KGS'i Box was orders of magnitude less potent than RGS4 in inhibiting agonist dependent a24 -ignalmg. Potency of inhibition and receptor selectivity was partially re siored only upon addition of a Maa N terminal peptide with the RGS4 liox. 1 hese findings indicate thai RGS-1 regulates Gq class signaling through its (JAP attivity, mediated by the RGS Box. and receptor-selective inhibition, mediated bv the amino terminus. Both activities are required for high polencv inhibiliun of precH coupled (li) ignaling.