Structure and function of G protein-coupled receptors

G protein-coupled receptors all belong to one stmctural family, which is frequently referred to as the 7-TM receptor family. This name refers to the 7 a-helical transmembrane domains, which occur in all of these molecules. Variability is larger in the N-terminal and C-terminal parts and the loops intervening between the transmembrane domains, which are exposed to the extracellular and the cytoplasmic spaces, respectively. 

The signal is expired through the intrinsic GTP ase activity of the a subunit, which after some random time interval will cleave the GTP to GDP. This will cause the a subunit to fall back into its inactive conformation and leave the effector, which in turn will resume its previous functional state. It will then re-associate with the (3y dimer to complete the cycle and wait for the next round of activation event by the same or another receptor molecule. 

However, the phospholipase C cascade is not restricted to smooth muscle cells but is ubiquitous. 

While the more numerous and clear-cut regulatory activities of G proteins are associated with a subunits, the Py dimers may also influence some downstream effector. An example is the effect of the muscarinergic receptor on the activity 

---

Javitch JA, Shi L, Liapkis G. 2002. Use of the substituted cysteine accessibility method to study the structure and function of G protein-coupled receptors. Methods Enzymol 343 137-156. 

Vaidehi N, Floriano WB, Trabanino R, Hall SE, Freddolino P, Choi EJ, Zamanakos G, Goddard WA 111. Prediction of structure and function of G protein-coupled receptors. Proc. Natl. Acad. Sci. U.S.A. 2002 99 12622-12627. 

Strader CD, Fong TM, Tota MR et al (1994) Structure and function of G protein-coupled receptors. Annu Rev Biochem 63 101-132... 

Zamanakos, and W. A. I. Goddard, Proc. Natl. Acad. Sci. XJ.S.A. 99, 12622 (2002). Prediction of Structure and Function of G Protein-Coupled Receptors. 

Muscarinic acetylcholine receptors (mAChRs) form a class of cell surface receptors that are activated upon binding of the neurotransmitter, acetylcholine. Structurally and functionally, mAChRs are prototypical members of the superfamily of G protein-coupled receptors. Following acetylcholine binding, the activated mAChRs interact with distinct classes of heterotrimeric G proteins resulting in the activation or inhibition of distinct downstream signaling cascades. 

Ballosteros, J A. and Weinstein, H. (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations of G protein-coupled receptors. Methods in Neurosciences, 25, 366-428. 

Fanelli, F. and De Benedetti, P.G. (2005) Computational modeling approaches to structure-function analysis of G protein-coupled receptors. Chemical Reviews, 105, 3297-3351. 

Tao, Y. X. (2006) Inactivating mutations of G protein-coupled receptors and diseases structure-function insights and therapeutic implications. Pharmacol. Ther. Ill, 949-973. 

Schoneberg, T., Schulz, A., and Gudermann, T. (2002) The structural basis of G-protein-coupled receptor function and dysfunction in human diseases. Rev. Physiol. Biochem. Pharmacol. 144, 143-227. 

Kristiansen K. Molecular mechanisms of ligand binding, signalling, and regulation within the superfamily of G-protein-coupled receptors molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther 2004 103 21-80. 

Attwood, T. K., Croning, M. D. R. and Gaulton, A. (2001) Deriving structural and functional insights firom a ligand-based hierarchical classification of G protein-coupled receptors. Protein Eng 15, 7-12. 

Receptor desensitization may also be mediated by second-messenger feedback. For example, adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A protein kinase A can phosphorylate residues on receptors, resulting in inhibition of receptor function. For the B2 receptor, phosphorylation occurs on serine residues both in the third cytoplasmic loop and in the carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes. 

Fredholm BB, Arslan G, Halldner L, Kull B, Schulte G, Wasserman W (2000) Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 362(4—5) 364—374 Freedman NJ, Lefkowitz RJ (1996) Desensitization of G protein-coupled receptors. Recent Prog Horm Res 51 319-351... 

---