Regulation of phospholipase C-β1 GTPase-activating protein (GAP) function and relationship to Gq efficacy

Authors

  • Irene Litosch

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    1. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA
    • Address correspondence to: Irene Litosch, Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33101-6189, USA. Tel.: 3052435862. Fax: +13052434555. E-mail: ilitosch@med.miami.edu

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Abstract

How cells regulate Gq efficacy (initiation and termination of Gq signaling) to effect response remains a central question in pharmacology and drug discovery. Phospholipase C-β1 (PLC-β1) is an effector and a GTPase activating protein (GAP) specific to Gαq. The physiological function of PLC-β1 GAP remains unclear and controversial. GAPs are generally thought to function in deactivation of Gq signaling. However, PLC-β1 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-β1 GAP is context-dependent and regulated by phosphatidic acid (PA). PA stimulates PLC-β1 GAP activity. In the absence of ligand, PLC-β1 GAP does indeed deactivate Gq 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-β1 GAP to kinetically couple with GPCR GEF to increase signaling efficiency. We found that PA-increased Gq efficiency is dependent on signaling via the unique PLC-β1 PA binding domain. © 2013 IUBMB Life, 65(11):936–940, 2013

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