Review
G-protein-coupled receptors and signaling networks: emerging paradigms

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Abstract

G-protein-coupled receptors (GPCRs) constitute the largest family of cell-surface molecules involved in signal transmission. These receptors play key physiological roles and their dysfunction results in several diseases. Recently, it has been shown that many of the cellular responses mediated by GPCRs do not involve the sole stimulation of conventional second-messenger-generating systems, but instead result from the functional integration of an intricate network of intracellular signaling pathways. Effectors for GPCRs that are independent of G proteins have now also been identified, thus changing the conventional view of the GPCR–heterotrimeric-G-protein-associated effector. The emerging information is expected to help elucidate the most basic mechanism by which these receptors exert their numerous physiological roles, in addition to determining why the perturbation of their function results in many pathological conditions.

Section snippets

G proteins and GPCRs in normal cell growth and cancer

Many potent mitogens such as thrombin, lysophosphatidic acid (LPA), bombesin, vasopressin, bradykinin, substance K, acetylcholine receptor agonists, angiotensin II and others stimulate cell proliferation by acting on their cognate GPCRs in a variety of cell types 4, 5, 6. The discovery of the mas oncogene, whose protein product exhibits a typical heptahelical structure, provided a link between cellular transformation and GPCRs (Ref. 7). No activating mutations were found in mas but instead the

A network of MAPKs links GPCRs to the nucleus and beyond

Recent work has revealed that multiple intracellular signaling pathways mediate the proliferative effects of GPCRs. Among them, a family of closely related proline-targeted serine–threonine kinases, collectively known as extracellular signal-regulated kinases (ERKs) or MAPKs, appears to play a central role. Following phosphorylation by their immediate upstream MEK, members of the MAPK family translocate to the nucleus where they phosphorylate transcription factors, thereby regulating the

G-protein-independent signaling by heptahelical receptors

Several recent provocative reports have revealed that GPCRs can interact with a wide variety of intracellular molecules in addition to heterotrimeric G proteins, thus broadening the molecular mechanisms by which these receptors transduce environmental signals. For example, the adaptor molecule arrestin binds many phosphorylated GPCRs and is primarily involved in targeting these receptors for endocytosis. However, arrestin has also been shown to couple GPCRs to the activation of Src-like kinases

Conclusions: unraveling the complexity of GPCR-mediated signaling pathways

The complexity of the molecular mechanisms whereby GPCRs transduce environmental signals has just begun to be fully appreciated. For a long time, the study of GPCR signaling has been focused on classical second-messenger-generating systems. However, we now realize that these intracellular signaling molecules are not sufficient to explain their wide array of biological responses. Instead, each GPCR would be expected to stimulate not one but a large number of highly interconnected cytoplasmic

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