GPR39抑制神经病理性疼痛的分子机制

甘氨酸受体的α1亚基大量表达于脊髓背角，产生抑制性的突触电流，控制着痛觉信息的传递与整合。甘氨酸受体的抑制功能减弱(即：“去”抑制)，是神经损伤诱发病理性疼痛的关键因素。因此，深入揭示甘氨酸受体的调控机制，将有望发现新的镇痛靶点。以往的研究表明：二价锌离子(Zn2+)具有明确的镇痛作用。申请人预实验发现：一种Zn2+敏感的G蛋白偶联受体----GPR39，能够特异性增强α1的突触传递，有效缓解病理性疼痛症状。引人注意的是：不同于传统的G蛋白偶联受体，GPR39对α1的增强作用，并不依赖于G蛋白信号通路。申请人发现：细胞膜上的GPR39，可能通过一种直接的“碰撞-去抑制”模式，打断α1与一种磷酸酶----蛋白酪氨酸磷酸酶-1B(PTP1B)的相互作用，解除PTP1B对α1的去磷酸化抑制，从而实现对α1的特异性调控。本项目的研究目标，在于深入揭示GPR39的非G蛋白依赖性的镇痛作用机制。

Glycine receptor α1 subunit is abundant in spinal cord dorsal horn, which generates inhibitory synaptic currents and controls the transmission and integration of nociceptive information. The impairment of glycinergic inhibition (disinhibition) is critical for nerve injury to cause neuropathic pain. Therefore, the deep research on the mechanisms underlying glycinergic disinhibition is helpful to find new therapeutic target for the treatment of neuropathic pain. Previous studies have shown that divalent zinc ion (Zn2+) can produce unambiguous analgesia against neuropathic pain. Our preliminary experiments found that GPR39, a Zn2+-sensitive G protein-coupled receptor, was able to specifically potentiate α1 synaptic currents and effectively alleviate neuropathic pain. It was noteworthy that, different from classic G protein-coupled receptors, the potentiation of α1 currents by GPR39 was independent of G protein signals. We found that transmembrane GPR39 might act through a direct “collision-disinhibition”mode to disturb α1 association with protein tyrosine phosphatase-1B (PTP1B). As a result, PTP1B was unable to dephosphorylate and inhibit α1, leading to a specific enhancement of α1 currents. This project aims to study the G protein-independent mechanisms underlying the analgesic action of GPR39 in depth.