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PMID: 22071319 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Pain ·Vol. 153 ·No. 1 ·2012-01-00 ·Pages 184-196

Tappe-Theodor A, Constantin CE, Tegeder I, Lechner SG, Langeslag M, Lepcynzsky P, Wirotanseng RI, Kurejova M, Agarwal N, Nagy G, Todd A, Wettschureck N, Offermanns S, Kress M, Lewin GR, 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), G₁₂/₁₃, 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)/G₁₁ 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 G₁₁ 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)/G₁₁ 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.

MeSH Terms
Animals Cells, Cultured GTP-Binding Protein alpha Subunits, Gq-G11/genetics,metabolism Ganglia, Spinal/cytology,metabolism,physiopathology Hyperalgesia/metabolism,physiopathology Mice Mice, Knockout Neurons/cytology,physiology Nociception/physiology Nociceptors/physiology Pain Measurement Protein Kinase C/metabolism Signal Transduction/physiology Type C Phospholipases/metabolism
Chemicals
Protein Kinase C Type C Phospholipases GTP-Binding Protein alpha Subunits, Gq-G11
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Tappe-Theodor Anke
Pharmacology Institut, University of Heidelberg, Heidelberg, Germany Department of Physiology and Medical Physics, Division of Physiology, Innsbruck Medical University, Innsbruck, Austria Pharmazentrum Frankfurt, Klinikum der Goethe-Universität, Frankfurt am Main 60590, Germany Max-Delbrueck-Center for Molecular Medicine, Department of Neurosciences, Berlin 13125, Germany Spinal Cord Group, West Medical Building, University of Glasgow, University Avenue, Glasgow, UK.
Constantin Cristina E
Tegeder Irmgard
Lechner Stefan G
Langeslag Michiel
Lepcynzsky Peter
Wirotanseng Richard I
Kurejova Martina
Agarwal Nitin
Nagy Gergely
Todd Andrew
Wettschureck Nina
Offermanns Stefan
Kress Michaela
Lewin Gary R
Kuner Rohini
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Article Info
Journal
Pain
Abbr.
Pain
ISSN
1872-6623
DOI
10.1016/j.pain.2011.10.014
Published
2012-01-00
Epub
2011-00-08
Pages
184-196
Language
English
Region
United States
NLM ID
7508686
Subset
IM
External Links
PubMed source DOI: 10.1016/j.pain.2011.10.014 View journal details
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