Signaling by G Protein-Coupled Receptors

Signaling is initiated by binding of an extracellular ligand, which produces a conformational change in the receptor that allows it to bind to the heterotrimeric G protein. 

Both a and Py can bind to and regulate the activity of various effectors of 

The signal is shut off by the action of the intrinsic GTPase activity of the a subunit, which catalyzes hydrolysis of the bound GTP to GDP and P,. 

The family of heterotrimeric G proteins that mediate signals from various cell- 

Second messengers mediate activation of signaling pathways downstream of the G protein-coupled receptors. 

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Bohm SK, Grady EF, Bunnett NW (1997) Regulatory mechanisms that modulate signalling by G-protein-coupled receptors. Biochem J 322 1-18... 

Luttrell LM (2006) Transmembrane signaling by G protein-coupled receptors. Methods Mol Biol 332 3—49... 

Meyer zu Heiingdoif, D.M., Lass, H., Alemany, R., Laser, K.T., Neumann, R, Zhang, C., Schmidt, M., Rauen, Lf., Jakobs, K.H. and Van Koppen, C.J., 1998, Sphingosine kinase-mediated signaling by G-protein-coupled receptors, EMBO J. 17 2830-2837. 

In addition, physical stimuli such as light signals are registered and converted into intracellular signals by G-protein coupled receptors they are also involved in perception of taste and smell. 

Sallese, M., Mariggio, S., D Urbano, E., Iacovelli, L., and De Blasi, A. (2000). Selective regulation of Gq signaling by G protein-coupled receptor kinase 2 Direct interaction of kinase N terminus with activated Gaq. Mol. Pharmacol. 57, 826-831. 

Daub H, Weiss FU, Wallasch C, Ullrich A. 1996. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379 557-560. 

Signalling by G-protein-coupled receptors is terminated by binding of the receptor kinase to the receptor, followed by phosphorylation. Receptor kinases are serine/threonine kinases, recognizing the active conformation of the receptor. A carrier function is attributed to Py-subunits in bringing the kinase to the receptor in the membrane. 25 For that function, isoprenylation of the Py-complex is required. This function is comparable to that of Ras, bringing the cytosolic Raf kinase to the membrane for activation. Both the y-subunits of the Py-complex and Ras are modified by prenylation (see Chapter 3). Control of G proteins by RGS proteins... 

Iacovelli L, Franchetti R, Grisolia D, De Blasi A. Selective regulation of G protein-coupled receptor-mediated signaling by G protein-coupled receptor kinase 2 in FRTL-5 cells analysis of thyrotropin, a1B-adrenergic, and Al adenosine receptor-mediated responses. Mol Pharmacol 1999 56 316-324. 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

Tollin, G. Salamon, Z. Cowell, S. M. Hruby, V. J., Plasmon waveguide resonance spectros copy A new tool for investigating signal transduction by G protein coupled receptors, Life Sci. 2003, 73, 3307 3311... 

Figure 14-1. Signaling via G protein-coupled receptors. Ligand binding to its cell-surface receptor initiates interaction of the receptor with the heterotrimeric G protein for which it is specific. A conformational change in the G protein brought about by binding of the ligand-receptor complex promotes exchange of GDP for GTP. The activated Gd-GTP dissociates from the Gp complex and both can interact with effectors, which carry on the signal to the mechanism that implements the cellular response.

Calcium and DAG are second messengers that mediate some responses initiated by signaling from G protein-coupled receptors (Figure 14—3). 

Sato M, Kataoka R, Dingus J, Wilcox M, Hildebrandt J, Lanier SM (1995) Factors determining speciUcity of signal transduction by G-protein-coupled receptors. IV. Regulation of signal transfer from receptor to G-protein. J Biol Chem 270 15269-15276... 

Aside from the regulation of G-protein activity by RGS proteins, signaling through G protein-coupled receptors can also be regulated at the level of the receptor itself (see Deutch and Roth, 1999). Such regulation occurs through several well-characterized mechanisms (Fig. 3.3). Within seconds to minutes of agonist acti-... 

Intracellular signal transduction employs central switching stations that receive, modulate and transmit signals further. The Ras proteins (also known as p2T proteins) make up a switching station of particular importance for growth and differentiation processes. The Ras proteins process signals received by receptor tyrosine kinases, by receptors with associated tyrosine kinase activity and by G-protein-coupled receptors, and transmit these into the cell interior (Fig. 9.1). 

Fig. 9.12. Overview of the Ras signaling pathway. Signals from at least three major signaling pathways meet at the Ras protein. Activation of the Ras protein may be initiated by receptor tyrosine kinases, by G-protein-coupled receptors and by receptors with associated tyrosine kinases. The nature of the communication between the Ras protein and receptors with associated tyrosine kinase or G-protein-coupled receptors is mostly unknown. From the activated Ras protein, the signal is passed to various effector molecules including members of the MEK kinases, PI3-kinase, pl20 GAP and Ral-GEFs. The best understood is the effector function of Raf kinase, which passes a signal to the transcription level via the MAP kinase pathway.

In vitro, urotensin II is a potent constrictor of vascular smooth muscle its activity depends on the type of blood vessel and the species from which it was obtained. Vasoconstriction occurs primarily in arterial vessels, where urotensin II can be more potent than endothelin 1, making it the most potent known vasoconstrictor. In vivo, urotensin II has complex hemodynamic effects, the most prominent being regional vasoconstriction and cardiac depression. The extent to which the peptide is involved in the regulation of vascular tone and blood pressure in humans is not clear recent studies have produced conflicting results. The actions of urotensin II are mediated by G protein-coupled receptors that are widely distributed in the brain, spinal cord, heart, vascular smooth muscle, skeletal muscle, and pancreas. Some effects of the peptide including vasoconstriction are mediated by the phospholipase C/IP3/DAG signal transduction pathway. 

In all systems studied thus far, olfactory-stimulated signal transduction is mediated by G-protein-coupled receptor (GPCR) pathways involving the synthesis of second messengers such as cyclic AMP (cAMP) and/or inositol 1,4,5-triphosphate (IP3) (Boekhoff et al., 1994 Reed, 1992). Moreover, several proteins that are involved in fundamental aspects of olfactory signal transduction have... 

Sadoshima, J., Qiu, Z., Morgan, J.P., and Izumo, S. 1995. Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes The critical role of Ca2+-dependent signaling. Circ. Res. 76 1-15. 

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