Details

Autor(en) / Beteiligte

• Hanack, Christina
• Moroni, Mirko
• Lima, Wanessa C.
• Wende, Hagen
• Kirchner, Marieluise
• Adelfinger, Lisa
• Schrenk-Siemens, Katrin
• Tappe-Theodor, Anke
• Wetzel, Christiane
• Kuich, P. Henning
• Gassmann, Martin
• Roggenkamp, Dennis
• Bettler, Bernhard
• Lewin, Gary R.
• Selbach, Matthias
• Siemens, Jan

Titel

GABA Blocks Pathological but Not Acute TRPV1 Pain Signals

Ist Teil von

• Cell, 2015-02, Vol.160 (4), p.759-770

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

ScienceDirect

Beschreibungen/Notizen

• 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. [Display omitted] •GABAB1 forms a complex with TRPV1 to counteract inflammatory pain•GABAB1 modulates TRPV1 via a non-canonical, GABAB2-independent pathway•TRPV1 activation triggers GABA release from peripheral nerve endings•GABA serves as a modulator of nociceptor sensitization in the periphery The neurotransmitter GABA is released upon stimulation of the pain receptor TRPV1 and engages a non-canonical signaling pathway that inhibits only hyperactive TRPV1, leaving homeostatic pain responses intact.