Spinal Inhibition of GABAB Receptors by the Extracellular Matrix Protein Fibulin-2 in Neuropathic Rats

Marie-Amélie Papon, Yves Le Feuvre, Gabriel Barreda-Gómez, Alexandre Favereaux, Fanny Farrugia, Rabia Bouali-Benazzouz, Frédéric Nagy, Rafael Rodríguez-Puertas, Marc Landry
Front. Cell. Neurosci.. 2020-07-15; 14:
DOI: 10.3389/fncel.2020.00214

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1. Front Cell Neurosci. 2020 Jul 15;14:214. doi: 10.3389/fncel.2020.00214.
eCollection 2020.

Spinal Inhibition of GABAB Receptors by the Extracellular Matrix Protein
Fibulin-2 in Neuropathic Rats.

Papon MA(1)(2), Le Feuvre Y(1)(2), Barreda-Gómez G(3), Favereaux A(1)(2),
Farrugia F(1)(2), Bouali-Benazzouz R(1)(2), Nagy F(1)(2), Rodríguez-Puertas R(3),
Landry M(1)(2).

Author information:
(1)Institut Interdisciplinaire de Neurosciences, University of Bordeaux,
Bordeaux, France.
(2)CNRS UMR 5297, Institut Interdisciplinaire de Neurosciences, Bordeaux, France.
(3)Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa,

In the central nervous system, the inhibitory GABAB receptor is the archetype of
heterodimeric G protein-coupled receptors (GPCRs). Receptor interaction with
partner proteins has emerged as a novel mechanism to alter GPCR signaling in
pathophysiological conditions. We propose here that GABAB activity is inhibited
through the specific binding of fibulin-2, an extracellular matrix protein, to
the B1a subunit in a rat model of neuropathic pain. We demonstrate that fibulin-2
hampers GABAB activation, presumably through decreasing agonist-induced
conformational changes. Fibulin-2 regulates the GABAB-mediated presynaptic
inhibition of neurotransmitter release and weakens the GABAB-mediated inhibitory
effect in neuronal cell culture. In the dorsal spinal cord of neuropathic rats,
fibulin-2 is overexpressed and colocalized with B1a. Fibulin-2 may thus interact
with presynaptic GABAB receptors, including those on nociceptive afferents. By
applying anti-fibulin-2 siRNA in vivo, we enhanced the antinociceptive effect of
intrathecal baclofen in neuropathic rats, thus demonstrating that fibulin-2
limits the action of GABAB agonists in vivo. Taken together, our data provide an
example of an endogenous regulation of GABAB receptor by extracellular matrix
proteins and demonstrate its functional impact on pathophysiological processes of
pain sensitization.

Copyright © 2020 Papon, Le Feuvre, Barreda-Gómez, Favereaux, Farrugia,
Bouali-Benazzouz, Nagy, Rodríguez-Puertas and Landry.

DOI: 10.3389/fncel.2020.00214
PMCID: PMC7378325
PMID: 32765223

Auteurs Bordeaux Neurocampus