Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Baclofen and other GABAB receptor agents are allosteric modulators of the CXCL12 chemokine receptor CXCR4.
Guyon A
,
Kussrow A
,
Olmsted IR
,
Sandoz G
,
Bornhop DJ
,
Nahon JL
.
???displayArticle.abstract??? CXCR4, a receptor for the chemokine CXCL12 (stromal-cell derived factor-1α), 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 antagonists and agonists block CXCL12-elicited chemotaxis in human breast cancer cells. Second, a GABAB antagonist blocks the potentiation by CXCL12 of high-threshold Ca(2+) channels in rat neurons. Third, electrophysiology in Xenopus oocytes and human embryonic kidney cell line 293 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. To investigate whether GABAB ligands bind to CXCR4, we expressed this receptor in heterologous systems lacking GABAB receptors and performed competition binding experiments. Our fluorescent resonance energy transfer experiments suggest that GABAB ligands do not bind CXCR4 at the CXCL12 binding pocket suggesting allosteric modulation, in accordance with our electrophysiology experiments. Finally, using backscattering interferometry and lipoparticles containing only the CXCR4 receptor, we quantified the binding affinity for the GABAB ligands, confirming a direct interaction with the CXCR4 receptor. The effect of GABAergic agents on CXCR4 suggests new therapeutic potentials for neurological and immune diseases.
Addolorato,
Baclofen: a new drug for the treatment of alcohol dependence.
2006, Pubmed
Addolorato,
Baclofen: a new drug for the treatment of alcohol dependence.
2006,
Pubmed
Azuma,
Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism.
2003,
Pubmed
Baksh,
Label-free quantification of membrane-ligand interactions using backscattering interferometry.
2011,
Pubmed
Banisadr,
Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in cholinergic and dopaminergic neurons.
2002,
Pubmed
Bhattacharyya,
The chemokine stromal cell-derived factor-1 regulates GABAergic inputs to neural progenitors in the postnatal dentate gyrus.
2008,
Pubmed
Bonavia,
Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation.
2003,
Pubmed
Bowery,
GABAB receptor pharmacology.
1993,
Pubmed
Busillo,
Regulation of CXCR4 signaling.
2007,
Pubmed
Busillo,
Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling.
2010,
Pubmed
Carbajal,
Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis.
2010,
Pubmed
Choi,
Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases.
2011,
Pubmed
Comerford,
Mini-review series: focus on chemokines.
2011,
Pubmed
Doranz,
Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1).
1997,
Pubmed
Duthey,
Anti-inflammatory effects of the GABA(B) receptor agonist baclofen in allergic contact dermatitis.
2010,
Pubmed
Entschladen,
Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters.
2004,
Pubmed
Froestl,
Chemistry and pharmacology of GABAB receptor ligands.
2010,
Pubmed
Gabuzda,
Chemokine receptors and mechanisms of cell death in HIV neuropathogenesis.
2000,
Pubmed
Gao,
Pancreatic stellate cells increase the invasion of human pancreatic cancer cells through the stromal cell-derived factor-1/CXCR4 axis.
2010,
Pubmed
Guglani,
Enteral baclofen in the management of tetanus-related spasms: case report and review of literature.
2007,
Pubmed
Guyon,
Stromal-cell-derived factor 1alpha /CXCL12 modulates high-threshold calcium currents in rat substantia nigra.
2008,
Pubmed
Guyon,
Modulation by different GABAB receptor types of voltage-activated calcium currents in rat thalamocortical neurones.
1995,
Pubmed
Guyon,
Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity.
2007,
Pubmed
Guyon,
Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms.
2006,
Pubmed
Han,
Wound healing activity of gamma-aminobutyric Acid (GABA) in rats.
2007,
Pubmed
Johnson,
Agonist-selective mechanisms of mu-opioid receptor desensitization in human embryonic kidney 293 cells.
2006,
Pubmed
Jones,
Cell-free assay of G-protein-coupled receptors using fluorescence polarization.
2008,
Pubmed
Juarez,
Chemokines and their receptors as therapeutic targets: the role of the SDF-1/CXCR4 axis.
2004,
Pubmed
Kaupmann,
GABA(B)-receptor subtypes assemble into functional heteromeric complexes.
1998,
Pubmed
,
Xenbase
Kolaski,
Intrathecal baclofen in cerebral palsy: A decade of treatment outcomes.
2008,
Pubmed
Laviv,
Compartmentalization of the GABAB receptor signaling complex is required for presynaptic inhibition at hippocampal synapses.
2011,
Pubmed
Lazarini,
Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system.
2003,
Pubmed
Li,
Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology.
2008,
Pubmed
Liu,
Regulation of the chemokine receptor CXCR4 and metastasis by hypoxia-inducible factor in non small cell lung cancer cell lines.
2006,
Pubmed
Madani,
gp120 envelope glycoproteins of human immunodeficiency viruses competitively antagonize signaling by coreceptors CXCR4 and CCR5.
1998,
Pubmed
,
Xenbase
Ortega,
A new role for GABA: inhibition of tumor cell migration.
2003,
Pubmed
Osawa,
Functional expression of the GABAB receptor in human airway smooth muscle.
2006,
Pubmed
Peterson,
Stem cell therapy for neurological disease and injury.
2004,
Pubmed
Plassat,
Treatment of spasticity with intrathecal Baclofen administration: long-term follow-up, review of 40 patients.
2004,
Pubmed
Qu,
Enhanced migration and CXCR4 over-expression in fibroblasts with telomerase reconstitution.
2008,
Pubmed
Rane,
Gamma-amino butyric acid type B receptors stimulate neutrophil chemotaxis during ischemia-reperfusion.
2005,
Pubmed
Rekand,
Treatment of spasticity related to multiple sclerosis with intrathecal baclofen: a long-term follow-up.
2011,
Pubmed
Rempel,
Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma.
2000,
Pubmed
Rostène,
Chemokines and chemokine receptors: new actors in neuroendocrine regulations.
2011,
Pubmed
Salcedo,
Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses.
2003,
Pubmed
Schönemeier,
Regional and cellular localization of the CXCl12/SDF-1 chemokine receptor CXCR7 in the developing and adult rat brain.
2008,
Pubmed
Seidel,
The neurotransmitter GABA is a potent inhibitor of the stromal cell-derived factor-1alpha induced migration of adult CD133+ hematopoietic stem and progenitor cells.
2007,
Pubmed
Shepherd,
Distinct modifications in Kv2.1 channel via chemokine receptor CXCR4 regulate neuronal survival-death dynamics.
2012,
Pubmed
Tatsuta,
Inhibition by gamma-amino-n-butyric acid and baclofen of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.
1990,
Pubmed
Tian,
Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model.
2004,
Pubmed
Tran,
The HIV-1 coat protein gp120 regulates CXCR4-mediated signaling in neural progenitor cells.
2005,
Pubmed
Uezono,
Activation of inwardly rectifying K+ channels by GABA-B receptors expressed in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Vinader,
An agarose spot chemotaxis assay for chemokine receptor antagonists.
2011,
Pubmed
Wang,
Roles of chemokine CXCL12 and its receptors in ischemic stroke.
2012,
Pubmed
Wang,
The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis.
2006,
Pubmed
Wang,
Baclofen, a GABAB receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo.
2008,
Pubmed
Yang,
[Current responses mediated by endogenous GABA(B) and GABA(C) receptors in Xenopus oocytes].
2001,
Pubmed
,
Xenbase
Zhang,
A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists.
2002,
Pubmed
Zhao,
Transforming growth factor-beta1 upregulates the expression of CXC chemokine receptor 4 (CXCR4) in human breast cancer MCF-7 cells.
2010,
Pubmed
