Gα(q/11) signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization

Item Type:	Article
Title:	Gα(q/11) signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization
Creators Name:	Tappe-Theodor, A. and Constantin, C.E. and Tegeder, I. and Lechner, S.G. and Langeslag, M. and Lepcynzsky, P. and Wirotanseng, R.I. and Kurejova, M. and Agarwal, N. and Nagy, G. and Todd, A. and Wettschureck, N. and Offermanns, S. and Kress, M. and Lewin, G.R. and Kuner, R.
Abstract:	Peripheral injury or inflammation leads to a release of mediators capable of binding to a variety of ion channels and receptors. Among these are the 7-transmembrane receptors (G protein-coupled receptors) coupling to G(s), G(i/o), G(12/13), or G(q/11) G proteins. Each of the G protein-coupled receptor pathways is involved in nociceptive modulation and pain processing, but the relative contribution of individual signaling pathways in vivo has not yet been worked out. The G(q)/G(11) signaling branch is of particular interest because it leads to the activation of phospholipase C-β, protein kinase C, the release of calcium from intracellular stores, and it modulates extracellular regulated kinases. To investigate the contribution of the entire G(q/11)-signaling pathway in nociceptors towards regulation of pain, we generated double-deficient mice lacking G(q/11) selectively in nociceptors using a conditional gene-targeting approach. We observed that nociceptor-specific loss of G(q) and G(11) results in reduced pain hypersensitivity following paw inflammation or spared nerve injury. Surprisingly, our behavioral and electrophysiological experiments also indicated defects in basal mechanical sensitivity in G(q/11) mutant mice, suggesting a novel function for G(q/11) in tonic modulation of acute nociception. Patch-clamp recordings revealed changes in voltage-dependent tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels in nociceptors upon a loss of G(q/11), whereas potassium currents remained unchanged. Our results indicate that the functional role of the G(q)/G(11) branch of G-protein signaling in nociceptors in vivo not only spans sensitization mechanisms in pathological pain states, but is also operational in tonic modulation of basal nociception and acute pain.
Keywords:	G Protein-Coupled Receptor, Nociceptor, Pain, Knock-Out Mice, TTX-Resistant Sodium Channels, Animals, Mice
Source:	Pain
ISSN:	0304-3959
Publisher:	Elsevier
Volume:	153
Number:	1
Page Range:	184-196
Date:	January 2012
Official Publication:	https://doi.org/10.1016/j.pain.2011.10.014
PubMed:	View item in PubMed

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