CP Taylor Consulting, Chelsea, Michigan (C.P.T.) and Cambrium Group, Raleigh, North Carolina (E.W.H.)
CP Taylor Consulting, Chelsea, Michigan (C.P.T.) and Cambrium Group, Raleigh, North Carolina (E.W.H.).
J Pharmacol Exp Ther. 2020 Jul;374(1):161-174. doi: 10.1124/jpet.120.266056. Epub 2020 Apr 22.
The gabapentinoid drugs gabapentin and pregabalin (Neurontin and Lyrica) are mainstay treatments for neuropathic pain and preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the -subunit type 1 [ -1], or ) is the high-affinity binding site for gabapentin and pregabalin and is required for the efficacy of these drugs. The -1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that -1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of -methyl-d-aspartate-sensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to -1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT: It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the -1 protein. However, recent findings show that the -1 protein also interacts with -methyl-d-aspartate-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.
加巴喷丁类药物加巴喷丁和普瑞巴林（神经痛和乐瑞卡）是治疗神经病理性疼痛和预防局灶性癫痫的主要药物。这两种药物在动物模型和临床中彼此具有相似的作用。研究表明，一种最初被鉴定为电压门控钙通道辅助亚基的蛋白质（ -1 亚基类型 1 [ -1]，或 ）是加巴喷丁和普瑞巴林的高亲和力结合位点，也是这些药物疗效所必需的。 -1 蛋白是加巴喷丁和普瑞巴林减少神经元组织神经递质释放的能力所必需的，这与通过电压门控钙通道发挥治疗作用的机制一致。然而，最近的研究表明， -1 除了与电压门控钙通道相互作用外，还与几种蛋白质相互作用，这些额外的蛋白质可能参与加巴喷丁类药物的药理学。此外，加巴喷丁和普瑞巴林已被证明通过与 -1 结合来改变一组 -甲基-d-天冬氨酸敏感型谷氨酸受体、神经连接蛋白-1 和血栓素蛋白的作用。因此，这些作用可能对加巴喷丁类药物的治疗机制产生重要影响。
人们普遍认为，加巴喷丁和普瑞巴林通过与 -1 蛋白结合，适度减少脊髓和新皮层突触末端电压门控钙通道的膜定位和激活，从而发挥作用。然而，最近的发现表明， -1 蛋白还与 -甲基-d-天冬氨酸敏感型谷氨酸受体、神经连接蛋白-1α、血栓素（粘附分子）和其他突触前蛋白相互作用。这些新发现的相互作用，除了在钙通道的作用外，可能是加巴喷丁和普瑞巴林治疗效果的重要介导物。
