Details

Autor(en) / Beteiligte

• Laffray, Sophie
• Bouali-benazzouz, Rabia
• Papon, Marie-amélie
• 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

Titel

Impairment of GABAB receptor dimer by endogenous 14-3-3[zeta] in chronic pain conditions

Ist Teil von

• The EMBO journal, 2012-08, Vol.31 (15), p.3239

Ort / Verlag

Heidelberg: Blackwell Publishing Ltd

Erscheinungsjahr

2012

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [PUBLICATION ABSTRACT]