Baclofen and Other GABAB Receptor Agents Are Allosteric Modulators of the CXCL12 Chemokine Receptor CXCR4
The Journal of Neuroscience, July 10, 2013 • 33(28):11643–11654 • 11643 Cellular/Molecular Baclofen and Other GABAB Receptor Agents Are Allosteric Modulators of the CXCL12 Chemokine Receptor CXCR4 Alice Guyon,1,2,3 Amanda Kussrow,4 Ian Roys Olmsted,4 Guillaume Sandoz,1,2,5 Darryl J. Bornhop,4* and Jean-Louis Nahon1,2,6* 1Universite´ de Nice Sophia Antipolis, 06103 Nice, France, 2Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Mole´culaire et Cellulaire, UMR 7275, 06560 Valbonne, France, 3Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720, 4Vanderbilt Institute of Chemical Biology, Nashville, Tennessee 37235-1822, 5Institute of Biology Valrose, CNRS UMR 7277, INSERM UMR 1091, Laboratories of Excellence, Ion Channel Science and Therapeutics, 06103 Nice, France, 6Station de Primatologie—UPS 846—Centre CNRS, RD56, 13790 Rousset sur Arc, France CXCR4, a receptor for the chemokine CXCL12 (stromal-cell derived factor-1␣), is a G-protein-coupled receptor (GPCR), expressed in the immune and CNS and integrally involved in various neurological disorders. The GABAB receptor is also a GPCR that mediates metabotropic action of the inhibitory neurotransmitter GABA and is located on neurons and immune cells as well. Using diverse approaches, we report novel interaction between GABAB receptor agents and CXCR4 and demonstrate allosteric binding of these agents to CXCR4. First, both GABAB antagonistsandagonistsblockCXCL12-elicitedchemotaxisinhumanbreastcancercells.Second,aGABAB antagonistblocksthepotentiationby CXCL12ofhigh-thresholdCa 2ϩ channelsinratneurons.Third,electrophysiologyinXenopusoocytesandhumanembryonickidneycellline293 ϩ cells in which we coexpressed rat CXCR4 and the G-protein inward rectifier K (GIRK) channel showed that GABAB antagonist and agonist modified CXCL12-evoked activation of GIRK channels.
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