Section 10
Chapter 9,581

The functional role of the binding site aspartate in muscarinic acetylcholine receptors, probed by site-directed mutagenesis

Page, K.M.; Curtis, C.A.; Jones, P.G.; Hulme, E.C.

European Journal of Pharmacology 289(3): 429-437


ISSN/ISBN: 0014-2999
PMID: 7556411
DOI: 10.1016/0922-4106(95)90151-5
Accession: 009580110

Mutation of the Asp in transmembrane domain three of the muscarinic receptors to Asn (M-1) or Glu (M-1 and M-2) strongly reduced the high-affinity component of agonist binding, and the M-1 phosphoinositide response. Formation of the acetylcholine-receptor binary complex was also strongly inhibited. In contrast, binary complex formation by other agonists, as well as the antagonist (-)-N-methylscopolamine, was less affected. Ionic bonding between the carboxylate oxyanion and the positively-charged headgroup probably anchors acetylcholine when it is bound in its active conformation, but alternative, non-productive, binding modes, promoted by non-polar forces, may contribute to binary complex formation by other ligands.

PDF emailed within 0-6 h: $19.90