GPCR downstream signalling

G protein-coupled receptors (GPCRs) are classically defined as the receptor, G-protein and downstream effectors, the alpha subunit of the G-protein being the primary signaling molecule. However, it has become clear that this greatly oversimplifies the complexities of GPCR signaling (Gurevich & Gurevich 2008). The beta:gamma G-protein dimer is also involved in downstream signaling (Smrcka 2008) and some receptors form metastable complexes with accessory proteins such as the arrestins.

GPCRs are involved in many diverse signaling events (Kristiansen 2004), using a variety of pathways that include modulation of adenylyl cyclase, phospholipase C, the mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK) c-Jun-NH2-terminal kinase (JNK) and p38 MAPK. Regulator of G-protein Signalling (RGS) proteins can directly inhibit the activity of the G-alpha subunit (Soundararajan et al. 2008).

The general function of the G alpha-s subunit (Gs) is to activate adenylate cyclase (Tesmer et al. 1997), which in turn produces cyclic-AMP (cAMP), leading to the activation of cAMP-dependent protein kinases (often referred to collectively as Protein Kinase A). The signal from the ligand-stimulated GPCR is amplified because the receptor can activate several Gs heterotrimers before it is inactivated.

The classical signalling mechanism for G alpha-i (Gi) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer et al. 2002). Decreased production of cAMP results in decreased activity of cAMP-dependent protein kinases.

G alpha-z (Gz) is a member of the Gi family. Unlike other Gi family members it is pertussis toxin-insensitive. Gz interacts with Rap1 GTPase activating protein (RAP1GAP) to attenuate Rap1 signaling.

The classic signalling route for G alpha-q (Gq) is activation of phospholipase C beta, leading to phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinases and many other proteins.

The G-alpha-12/13 (G12/13) family is probably the least well characterized, at least in part because G12/13 coupling is more difficult to determine than for other subtypes, G12/13 is best known for involvement in the processes of cell proliferation and morphology, such as stress fiber and focal adhesion formation. Interactions with Rho guanine nucleotide exchange factors (RhoGEFs) are thought to mediate many of these processes. (Buhl et al.1995, Sugimoto et al. 2003). Activation of Rho or the regulation of events through Rho is often taken as evidence of G12/13 signaling. Receptors that are coupled with G12/13 invariably couple with one or more other G protein subtypes, usually Gq.

G蛋白偶联受体（GPCRs）被经典定义为受体、G蛋白及下游效应器，其中G蛋白的α亚基作为主要的信号分子。然而，这一概念极大地简化了GPCR信号传导的复杂性（Gurevich & Gurevich 2008）。β:γ G蛋白二聚体也参与下游信号传导（Smrcka 2008），且某些受体与辅助蛋白，如抑制蛋白（arrestins）形成亚稳态复合物。GPCRs参与众多多样的信号事件（Kristiansen 2004），通过多种途径实现调节，包括腺苷酸环化酶、磷脂酶C、丝裂原活化蛋白激酶（MAPKs）、细胞外信号调节激酶（ERK）、c-Jun-NH2末端激酶（JNK）和p38 MAPK。G蛋白信号传导调节蛋白（RGS）可直接抑制G-α亚基的活性（Soundararajan et al. 2008）。G α-s 亚基（Gs）的一般功能是激活腺苷酸环化酶（Tesmer et al. 1997），进而产生环磷酸腺苷（cAMP），导致cAMP依赖性蛋白激酶（通常统称为蛋白激酶A）的激活。由于受体在失活前可以激活多个Gs异源三聚体，因此配体激活的GPCR信号得到放大。G α-i（Gi）的经典信号传导机制是通过抑制腺苷酸环化酶来抑制cAMP依赖性途径（Dessauer et al. 2002）。cAMP产量的减少导致cAMP依赖性蛋白激酶活性降低。G α-z（Gz）是Gi家族的成员。与其他Gi家族成员不同，它对百日咳毒素不敏感。Gz与Rap1 GTP酶活化蛋白（RAP1GAP）相互作用，以减弱Rap1信号传导。G α-q（Gq）的经典信号传导途径是激活磷脂酶C β，导致磷脂酰肌醇水解、钙动员和蛋白激酶C的激活。这为钙调节激酶和磷酸酶、GEFs、MAP激酶以及许多其他蛋白提供了通路。G-α-12/13（G12/13）家族可能是最不为人所知的，至少部分原因是与其它亚型相比，G12/13的偶联作用更难以确定。G12/13最著名的参与细胞增殖和形态过程，如应力纤维和粘附斑的形成。与Rho鸟苷酸交换因子（RhoGEFs）的相互作用被认为介导了许多这些过程。Rho或通过Rho调节事件的激活通常被视为G12/13信号传导的证据。与G12/13偶联的受体必然与一个或多个其他G蛋白亚型偶联，通常是Gq。