Chasse Scott A, Dohlman Henrik G
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Assay Drug Dev Technol. 2003 Apr;1(2):357-64. doi: 10.1089/154065803764958649.
Many drugs act on receptors coupled to heterotrimeric G proteins. Historically, drug discovery has focused on agents that bind to the receptors and either stimulate or inhibit the receptor-initiated signal. This is an approach that is both direct and logical, and has proven extremely fruitful in the past. However, as our understanding of G-protein signaling has increased, novel opportunities for drug development have emerged. RGS proteins are multifunctional GTPase-accelerating proteins that inactivate G-protein signaling pathways. GTPase-accelerating protein activity is a general feature of RGS proteins, and serves to facilitate the inactivation of the G protein rather than the receptor. Thus, agents that bind and inhibit RGS proteins could modulate endogenous neurotransmitter and hormone signaling, in a manner analogous to neurotransmitter uptake inhibitors. Here we discuss the potential of RGS proteins as drug targets.
许多药物作用于与异源三聚体G蛋白偶联的受体。从历史上看，药物研发主要集中在那些与受体结合并刺激或抑制受体启动信号的药物上。这是一种直接且合乎逻辑的方法，并且在过去已被证明极具成效。然而，随着我们对G蛋白信号传导的理解不断加深，药物开发出现了新的机遇。RGS蛋白是多功能的GTP酶加速蛋白，可使G蛋白信号通路失活。GTP酶加速蛋白活性是RGS蛋白的一个普遍特征，其作用是促进G蛋白而非受体的失活。因此，结合并抑制RGS蛋白的药物可以以内源性神经递质和激素信号类似的方式调节神经递质和激素信号。在此，我们讨论RGS蛋白作为药物靶点的潜力。
