The term is used to describe GTP-binding proteins. There are two classes of G-proteins, the small cytoplasmic G-proteins (Gh) and the hetero-trimeric G-proteins composed of different subunits (a,ß,?) that mediate the signal of heptahelical receptors (GPCRs). Agonist binding to GPCRs leads to association of the hetero-trimeric G protein with the receptor, GDP-GTP exchange in the G protein a subunit followed by dissociation of the G protein into a-GTP and ß? complexes. The dissociated subunits can activate or inhibit several effectors such as adenylyl cyclase, PLCß, tyrosine kinases, phosphodiesterases, phosphoinositide 3-kinase, GPCR kinases, ion channels, and molecules of the mitogen-activated protein kinase pathway, resulting in a variety of cellular functions. However, there is evidence that some GPCRs transduce their signal through in a way that is not G protein-dependent, and also that hetero-trimeric G proteins are involved in mediating the action of single-spanning membrane receptors.
Published in Chapter:
Computational Methods for the Prediction of GPCRs Coupling Selectivity
Nikolaos G. Sgourakis (Rensselaer Polytechnic Institute, USA), Pantelis G. Bagos (University of Central Greece, and University of Athens, Greece), and Stavros J. Hamodrakas (University of Athens, Greece)
Copyright: © 2009
|Pages: 15
DOI: 10.4018/978-1-60566-076-9.ch009
Abstract
GPCRs comprise a wide and diverse class of eukaryotic transmembrane proteins with well-established pharmacological significance. As a consequence of recent genome projects, there is a wealth of information at the sequence level that lacks any functional annotation. These receptors, often quoted as orphan GPCRs, could potentially lead to novel drug targets. However, typical experiments that aim at elucidating their function are hampered by the lack of knowledge on their selective coupling partners at the interior of the cell, the G-proteins. Up-to-date, computational efforts to predict properties of GPCRs have been focused mainly on the ligand-binding specificity, while the aspect of coupling has been less studied. Here, we present the main motivations, drawbacks, and results from the application of bioinformatics techniques to predict the coupling specificity of GPCRs to G-proteins, and discuss the application of the most successful methods in both experimental works that focus on a single receptor and large-scale genome annotation studies.