Mohan Maradumane L, Vasudevan Neelakantan T, Gupta Manveen K, Martelli Elizabeth E, Naga Prasad S V
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195.
Curr Mol Pharmacol. 2012 May 30.
G-protein coupled receptors (GPCRs) are seven transmembrane receptors that are pivotal regulators of cellular responses including vision, cardiac contractility, olfaction, and platelet activation. GPCRs have been a major target for drug discovery due to their role in regulating a broad range of physiological and pathological responses. GPCRs mediate these responses through a cyclical process of receptor activation (initiation of downstream signals), desensitization (inactivation that results in diminution of downstream signals), and resensitization (receptor reactivation for next wave of activation). Although these steps may be of equal importance in regulating receptor function, significant advances have been made in understanding activation and desensitization with limited effort towards resensitization. Inadequate importance has been given to resensitization due to the understanding that resensitization is a homeostasis maintaining process and is not acutely regulated. Evidence indicates that resensitization is a critical step in regulating GPCR function and may contribute towards receptor signaling and cellular responses. In light of these observations, it is imperative to discuss resensitization as a dynamic and mechanistic regulator of GPCR function. In this review we discuss components regulating GPCR function like activation, desensitization, and internalization with special emphasis on resensitization. Although we have used β-adrenergic receptor as a proto-type GPCR to discuss mechanisms regulating receptor function, other GPCRs are also described to put forth a view point on the universality of such mechanisms.
G蛋白偶联受体（GPCRs）是七跨膜受体，是细胞反应的关键调节因子，包括视觉、心脏收缩力、嗅觉和血小板激活。由于GPCRs在调节广泛的生理和病理反应中发挥作用，它们一直是药物研发的主要靶点。GPCRs通过受体激活（下游信号的启动）、脱敏（导致下游信号减弱的失活）和再敏化（为下一波激活而进行的受体再激活）的循环过程来介导这些反应。尽管这些步骤在调节受体功能方面可能同样重要，但在理解激活和脱敏方面已经取得了重大进展，而对再敏化的研究投入有限。由于人们认为再敏化是一个维持内稳态的过程，不受急性调节，因此对其重视不足。有证据表明，再敏化是调节GPCR功能的关键步骤，可能有助于受体信号传导和细胞反应。鉴于这些观察结果，有必要将再敏化作为GPCR功能的动态和机制调节因子进行讨论。在这篇综述中，我们讨论调节GPCR功能的组成部分，如激活、脱敏和内化，并特别强调再敏化。尽管我们使用β-肾上腺素能受体作为典型的GPCR来讨论调节受体功能的机制，但也描述了其他GPCRs，以提出关于这些机制普遍性的观点。
