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
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
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