QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Related Article All Versions of this Article: mol.105.019141v1 68/6/1506    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Related articles in MolPharm Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wess, J. Search for Related Content PubMed PubMed Citation Articles by Wess, J.

Perspective

Allosteric Binding Sites on Muscarinic Acetylcholine Receptors

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

In this issue of Molecular Pharmacology, Tränkle et al. (p. 1597) present new findings regarding the existence of a second allosteric site on the M₂ muscarinic acetylcholine receptor (M₂ mAChR). The M₂ mAChR is a prototypic class A G protein-coupled receptor (GPCR) that has proven to be a very useful model system to study the molecular mechanisms involved in the binding of allosteric GPCR ligands. Previous studies have identified several allosteric muscarinic ligands, including the acetylcholinesterase inhibitor tacrine and the bis-pyridinium derivative 4,4'-bis-[(2,6-dichloro-benzyloxy-imino)-methyl]-1,1'-propane-1,3-diyl-bis-pyridinium dibromide (Duo3), which, in contrast to conventional allosteric muscarinic ligands, display concentration-effect curves with slope factors >1. By analyzing the interactions of tacrine and Duo3 with other allosteric muscarinic agents predicted to bind to the previously identified `common' allosteric binding site, Tränkle et al. provide evidence suggesting that two allosteric agents and one orthosteric ligand may be able to bind to the M₂ mAChR simultaneously. Moreover, studies with mutant mAChRs indicated that the M₂ receptor epitopes involved in the binding of tacrine and Duo3 may not be identical. Molecular modeling and ligand docking studies suggested that the additional allosteric site probably represents a subdomain of the receptor's allosteric binding cleft. Because allosteric binding sites have been found on many other GPCRs and drugs interacting with these sites are thought to have great therapeutic potential, the study by Tränkle et al. should be of considerable general interest.

Address correspondence to: Dr. Jürgen Wess, Chief, Molecular Signaling Section, Lab. of Bioorganic Chemistry, NIH-NIDDK, Bldg. 8A, Room B1A-05, 8 Center Drive MSC 0810, Bethesda, MD 20892-0810. E-mail: jwess{at}helix.nih.gov

Related articles in MolPharm:

Atypical Muscarinic Allosteric Modulation: Cooperativity between Modulators and Their Atypical Binding Topology in Muscarinic M₂ and M₂/M₅ Chimeric Receptors

Christian Tränkle, Andreas Dittmann, Uwe Schulz, Oliver Weyand, Stefan Buller, Kirstin Jöhren, Eberhard Heller, Nigel J. M. Birdsall, Ulrike Holzgrabe, John Ellis, Hans Dieter Höltje, and Klaus Mohr
MolPharm 2005 68: 1597-1610. [Abstract] [Full Text]  

This article has been cited by other articles:

				W. Y. Chan, D. L. McKinzie, S. Bose, S. N. Mitchell, J. M. Witkin, R. C. Thompson, A. Christopoulos, S. Lazareno, N. J. M. Birdsall, F. P. Bymaster, et al. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia PNAS, August 5, 2008; 105(31): 10978 - 10983. [Abstract] [Full Text] [PDF]

				D. Jager, C. Schmalenbach, S. Prilla, J. Schrobang, A. Kebig, M. Sennwitz, E. Heller, C. Trankle, U. Holzgrabe, H.-D. Holtje, et al. Allosteric Small Molecules Unveil a Role of an Extracellular E2/Transmembrane Helix 7 Junction for G Protein-coupled Receptor Activation J. Biol. Chem., November 30, 2007; 282(48): 34968 - 34976. [Abstract] [Full Text] [PDF]

				S. Prilla, J. Schrobang, J. Ellis, H.-D. Holtje, and K. Mohr Allosteric Interactions with Muscarinic Acetylcholine Receptors: Complex Role of the Conserved Tryptophan M2422Trp in a Critical Cluster of Amino Acids for Baseline Affinity, Subtype Selectivity, and Cooperativity Mol. Pharmacol., July 1, 2006; 70(1): 181 - 193. [Abstract] [Full Text] [PDF]