Impairment of GABAB receptor dimer by endogenous 14-3-3ζ in chronic pain conditions.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

14-3-3 Proteins/*physiology ; Chronic Pain/*pathology ; Receptors, GABA-B/*metabolism; 14-3-3 Proteins/chemistry ; 14-3-3 Proteins/genetics ; 14-3-3 Proteins/metabolism ; Animals ; Cells, Cultured ; Chronic Pain/genetics ; Chronic Pain/metabolism ; Disease Models, Animal ; Neuralgia/genetics ; Neuralgia/metabolism ; Neuralgia/pathology ; Posterior Horn Cells/drug effects ; Posterior Horn Cells/metabolism ; Posterior Horn Cells/pathology ; Protein Binding/genetics ; Protein Binding/physiology ; Protein Interaction Domains and Motifs/drug effects ; Protein Multimerization/drug effects ; Protein Multimerization/genetics ; Protein Subunits/genetics ; Protein Subunits/metabolism ; RNA, Small Interfering/pharmacology ; Rats ; Rats, Transgenic ; Receptors, GABA-B/chemistry ; Receptors, GABA-B/genetics

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.

Comment in: EMBO J. 2012 Aug 1;31(15):3234-6. (PMID: 22735189)

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0 (14-3-3 Proteins)
0 (Protein Subunits)
0 (RNA, Small Interfering)
0 (Receptors, GABA-B)

Date Created: 20120614 Date Completed: 20121025 Latest Revision: 20220331

20231215

PMC3411072

10.1038/emboj.2012.161

22692127