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Regulation of phospholipase C‐β 1 GTPase‐activating protein (GAP) function and relationship to G q efficacy
Author(s) -
Litosch Irene
Publication year - 2013
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.1218
Subject(s) - g protein coupled receptor , gq alpha subunit , gtpase activating protein , phosphatidic acid , phospholipase c , g protein , microbiology and biotechnology , guanine nucleotide exchange factor , signal transduction , gtpase , phospholipase , context (archaeology) , biology , effector , ligand (biochemistry) , phospholipase d , biochemistry , chemistry , receptor , phospholipid , enzyme , paleontology , membrane
How cells regulate G q efficacy (initiation and termination of G q signaling) to effect response remains a central question in pharmacology and drug discovery. Phospholipase C‐β 1 (PLC‐β 1 ) is an effector and a GTPase activating protein (GAP) specific to Gα q . The physiological function of PLC‐β 1 GAP remains unclear and controversial. GAPs are generally thought to function in deactivation of G q signaling. However, PLC‐β 1 GAP has also been shown to increase signaling efficiency through kinetic coupling with the ligand‐activated GPCR. GPCRs function as guanine nucleotide exchange factors (GEF) on the G protein activation cycle. This article sets forth a new hypothesis that could unify these conflicting paradigms as it pertains to physiological signaling and native levels of protein. It is proposed that the physiological function of PLC‐β 1 GAP is context‐dependent and regulated by phosphatidic acid (PA). PA stimulates PLC‐β 1 GAP activity. In the absence of ligand, PLC‐β 1 GAP does indeed deactivate G q signaling, limiting leaky activation to set the threshold for stimulation to sharpen signal kinetics. However in the presence of activating ligand, the increase in levels of PA would stimulate PLC‐β 1 GAP to kinetically couple with GPCR GEF to increase signaling efficiency. We found that PA‐increased G q efficiency is dependent on signaling via the unique PLC‐β 1 PA binding domain. © 2013 IUBMB Life, 65(11):936–940, 2013