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Subtype-specific changes in ligand binding properties after solubilization of muscarinic receptors from baculovirus-infected Sf9 insect cell membranes

A Rinken

Department of Medical and Physiological Chemistry, University of Uppsala, Sweden.

Ligand binding properties of membrane-bound and solubilized muscarinic acetylcholine receptor (mAChR) subtypes (human m1 and m2; rat m3 and m4), produced by using a baculovirus infection system in Sf9 insect cells have been studied. Most of the studied ligands that have been proposed previously to be selective for some subtype had similar selectivity to mAChRs in Sf9 cell membranes. Only tropicamide, which has been proposed as m4-specific ligand, had higher affinity for m1. Solubilization of receptors decreased binding affinities of all studied ligands to m1 and m3 mAChR, on average 10- and 75-fold, respectively. The solubilization of m2 mAChR had only slight influence on the affinity of subtype nonspecific ligands, but decreased 5- to 10-fold the affinities of m2-specific ligands and increased up to 6-fold the affinities of m1- and m3-specific ligands. Effects of m4 mAChR were similar to those on m2, but without a decrease in affinities of m2- specific ligands. This combination of reduction and increase of binding affinities caused by solubilization led to loss of subtype selectivity of most ligands studied. Only AF-DX 116 [11-((2-[(diethylamino)-methyl]- 1- piperidinyl)-acetyl)-5,11-dihydro-6H-pyrido(2,3b)-(1,4)- benzodiazepin -6-ontelenzepine] and gallamine retained their selectivity for m2 after solubilization of mAChR. Incorporation of mAChR into brain membranes restored their subtype specificity in ligand binding. These data suggest that subtype-specific antagonist binding to mAChR is generally modulated by the lipid environment of receptor protein.

Volume 272, Issue 1, pp. 8-14, 01/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics




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