Impairment of GABAB receptor dimer by endogenous 14-3-3ζ in chronic pain conditions.
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.
Bordeaux University, Bordeaux, France.
Sophie
S
Laffray
Rabia
R
Bouali-Benazzouz
Marie-Amélie
MA
Papon
Alexandre
A
Favereaux
Yang
Y
Jiang
Tina
T
Holm
Corentin
C
Spriet
Pascal
P
Desbarats
Pascal
P
Fossat
Yves
Y
Le Feuvre
Marion
M
Decossas
Laurent
L
Héliot
Ulo
U
Langel
Frédéric
F
Nagy
Marc
M
Landry
D048948:14-3-3 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D059350:Chronic Pain / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D018080:Receptors, GABA-B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; D018080:Receptors, GABA-B