Abstract
Adhesion G protein-coupled receptors (GPCR), with their very large and complex N termini, are thought to participate in cell-cell and cell-matrix interactions and appear to be highly relevant in several developmental processes. Their intracellular signaling is still poorly understood. Here we demonstrate that GPR133, a member of the adhesion GPCR subfamily, activates the G(s) protein/adenylyl cyclase pathway. The presence of the N terminus and the cleavage at the GPCR proteolysis site are not required for G protein signaling. G(s) protein coupling was verified by Gα(s) knockdown with siRNA, overexpression of Gα(s), co-expression of the chimeric Gq(s4) protein that routes GPR133 activity to the phospholipase C/inositol phosphate pathway, and missense mutation within the transmembrane domain that abolished receptor activity without changing cell surface expression. It is likely that not only GPR133 but also other adhesion GPCR signal via classical receptor/G protein-interaction.
Highlights
Adhesion receptors comprise the second largest subfamily of putatively G protein-coupled receptors (GPCR)2 with more than 30 members in vertebrates [1, 2]
GPR133 Displays Increased Basal Activity in the Gs Protein/ Adenylyl Cyclase Pathway—According to the current model of GPCR function [25, 26], receptor overexpression can result in a constitutive activation of signaling pathways, which are normally activated after agonist stimulation [27,28,29,30]
The human and mouse GPR133 were transiently expressed in HEK293 cells and tested in AP1, nuclear factor of activated T-cells (NFAT), serum responsive element (SRE), and CRE-SEAP reporter gene assays
Summary
Adhesion receptors comprise the second largest subfamily of putatively G protein-coupled receptors (GPCR) with more than 30 members in vertebrates [1, 2]. There is consensus on the fact that this receptor class mediates essential cellcell and cell-matrix interactions [1, 12], the molecular mechanism of intracellular signal transduction of adhesion GPCR remains obscure. There are only a few studies on intracellular signaling mechanisms of adhesion GPCR. 41912 JOURNAL OF BIOLOGICAL CHEMISTRY sion GPCR, induces intracellular Ca2ϩ signaling upon interaction with the exogenous ligand ␣-latrotoxin [13, 14]. Clear evidence of intracellular signaling for most adhesion GPCR via G proteins is still missing [12]. We demonstrate that GPR133 is coupled to the Gs protein/adenylyl cyclase pathway. This proves that this adhesion receptor is a G protein-coupled receptor
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