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Impairment of GABAB receptor dimer by endogenous 14‐3‐3ζ in chronic pain conditions
Author(s) -
Laffray Sophie,
BoualiBenazzouz Rabia,
Papon MarieAmélie,
Favereaux Alexandre,
Jiang Yang,
Holm Tina,
Spriet Corentin,
Desbarats Pascal,
Fossat Pascal,
Le Feuvre Yves,
Decossas Marion,
Héliot Laurent,
Langel Ulo,
Nagy Frédéric,
Landry Marc
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.161
Subject(s) - biology , gabab receptor , endogeny , receptor , neuroscience , genetics , gabaa receptor , endocrinology
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 14‐3‐3ζ, 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, 14‐3‐3ζ is overexpressed and weakens GABAB inhibition. Using anti‐14‐3‐3ζ siRNA or competing peptides disrupts 14‐3‐3ζ/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.