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Spinal Inhibition of GABAB Receptors by the Extracellular Matrix Protein Fibulin-2 in Neuropathic Rats.
Frontiers in Cellular Neuroscience ( IF 4.2 ) Pub Date : 2020-06-17 , DOI: 10.3389/fncel.2020.00214
Marie-Amélie Papon 1, 2 , Yves Le Feuvre 1, 2 , Gabriel Barreda-Gómez 3 , Alexandre Favereaux 1, 2 , Fanny Farrugia 1, 2 , Rabia Bouali-Benazzouz 1, 2 , Frédéric Nagy 1, 2 , Rafael Rodríguez-Puertas 3 , Marc Landry 1, 2
Affiliation  

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.



中文翻译:

细胞外基质蛋白Fibulin-2在神经性大鼠中对GABA B受体的脊髓抑制作用。

在中枢神经系统中,抑制性GABAB受体是异二聚体G蛋白偶联受体(GPCR)的原型。受体与伴侣蛋白的相互作用已经成为一种在病理生理条件下改变GPCR信号传导的新机制。我们在这里提出,在神经性疼痛的大鼠模型中,GABA B活性是通过fibulin-2(一种细胞外基质蛋白)与B1a亚基的特异性结合而受到抑制的。我们证明,fibulin-2阻碍了GABA B的激活,大概是通过减少激动剂诱导的构象变化。Fibulin-2调节GABAB介导的神经递质释放的突触前抑制,并减弱GABAB介导的神经元细胞培养中的抑制作用。在神经性大鼠的背脊髓中,fibulin-2过度表达并与B1a共定位。因此,Fibulin-2可能与突触前GABA B受体(包括伤害性传入受体上的受体)相互作用。通过应用抗fibulin-2 siRNA体内,我们增强了鞘内巴氯芬对神经病大鼠的镇痛作用,从而证明fibulin-2限制了GABAB激动剂的作用 体内。综上所述,我们的数据提供了细胞外基质蛋白内源性调节GABA B受体的实例,并证明了其对疼痛致敏的病理生理过程的功能影响。

更新日期:2020-07-15
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