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Impairment of GABAB receptor dimer by endogenous 14-3-3 zeta in chronic pain conditions
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2012 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 31, no 15, 3239-3251 p.Article in journal (Refereed) Published
Abstract [en]

In the central nervous system, the inhibitory GABAB receptor is the archetype of heterodimeric G protein-coupled receptors (GPCRs). However, the regulation of GABAB dimerization, and more generally of GPCR oligomerization, remains largely unknown. We propose a novel mechanism for inhibition of GPCR activity through de-dimerization in pathological conditions. We show here that 14-3-3 zeta, a GABAB1-binding protein, dissociates the GABAB heterodimer, resulting in the impairment of GABAB signalling in spinal neurons. In the dorsal spinal cord of neuropathic rats, 14-3-3 zeta is overexpressed and weakens GABAB inhibition. Using anti-14-3-3 zeta siRNA or competing peptides disrupts 14-3-3 zeta/GABAB1 interaction and restores functional GABAB heterodimers in the dorsal horn. Importantly, both strategies greatly enhance the anti-nociceptive effect of intrathecal Baclofen in neuropathic rats. Taken together, our data provide the first example of endogenous regulation of a GPCR oligomeric state and demonstrate its functional impact on the pathophysiological process of neuropathic pain sensitization. The EMBO Journal (2012) 31, 3239-3251. doi:10.1038/emboj.2012.161; Published online 12 June 2012

Place, publisher, year, edition, pages
2012. Vol. 31, no 15, 3239-3251 p.
Keyword [en]
disinhibition, G protein-coupled receptor, neuropathic pain, oligomer, spinal cord
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-80622DOI: 10.1038/emboj.2012.161ISI: 000307116600004OAI: oai:DiVA.org:su-80622DiVA: diva2:556496
Note

AuthorCount:15;

Available from: 2012-09-25 Created: 2012-09-25 Last updated: 2017-12-07Bibliographically approved

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Langel, Ülo
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