title: GABA blocks pathological but not acute TRPV1 pain signals.
abstract: Sensitization of the capsaicin receptor TRPV1 is central to the initiation of pathological forms of pain, and multiple signaling cascades are known to enhance TRPV1 activity under inflammatory conditions. How might detrimental escalation of TRPV1 activity be counteracted? Using a genetic-proteomic approach, we identify the GABAB1 receptor subunit as bona fide inhibitor of TRPV1 sensitization in the context of diverse inflammatory settings. We find that the endogenous GABAB agonist, GABA, is released from nociceptive nerve terminals, suggesting an autocrine feedback mechanism limiting TRPV1 sensitization. The effect of GABAB on TRPV1 is independent of canonical G protein signaling and rather relies on close juxtaposition of the GABAB1 receptor subunit and TRPV1. Activating the GABAB1 receptor subunit does not attenuate normal functioning of the capsaicin receptor but exclusively reverts its sensitized state. Thus, harnessing this mechanism for anti-pain therapy may prevent adverse effects associated with currently available TRPV1 blockers.
authors: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: Christina
authors: C
authors: Hanack
authors: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: Mirko
authors: M
authors: Moroni
authors: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Wanessa C
authors: WC
authors: Lima
authors: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Hagen
authors: H
authors: Wende
authors: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: Marieluise
authors: M
authors: Kirchner
authors: Department of Biomedicine, University of Basel, CH-4056 Basel, Switzerland.
authors: Lisa
authors: L
authors: Adelfinger
authors: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Katrin
authors: K
authors: Schrenk-Siemens
authors: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Anke
authors: A
authors: Tappe-Theodor
authors: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: Christiane
authors: C
authors: Wetzel
authors: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: P Henning
authors: PH
authors: Kuich
authors: Department of Biomedicine, University of Basel, CH-4056 Basel, Switzerland.
authors: Martin
authors: M
authors: Gassmann
authors: Beiersdorf AG, Research & Development, Unnastrasse 48, 20245 Hamburg, Germany.
authors: Dennis
authors: D
authors: Roggenkamp
authors: Department of Biomedicine, University of Basel, CH-4056 Basel, Switzerland.
authors: Bernhard
authors: B
authors: Bettler
authors: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: Gary R
authors: GR
authors: Lewin
authors: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors: Matthias
authors: M
authors: Selbach
authors: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address: jan.siemens@pharma.uni-heidelberg.de.
authors: Jan
authors: J
authors: Siemens
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002478:Cells, Cultured; D005246:Feedback; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018080:Receptors, GABA-B; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D005680:gamma-Aminobutyric Acid