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Vol. 301, Issue 2, 720-728, May 2002

Allosteric Modulation of Muscarinic Receptor Signaling: Alcuronium-Induced Conversion of Pilocarpine from an Agonist into an Antagonist

Katrin Zahn, Niels Eckstein , Christian Tränkle, Wolfgang Sadée and Klaus Mohr

Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Germany (K.Z., N.E., C.T., K.M.); and Department of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California, San Francisco, California (N.E., W.S.)

Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M2 subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M2-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC50, Alc = 5.63) without any effect on the EC50 of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pKA, Alc = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 µM alcuronium. Measuring guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgamma S) binding in CHO-M2 membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [35S]GTPgamma S binding (pIC50, Alc = 5.47) without shift in EC50, whereas it competitively shifted the response to oxotremorine M (pKA, Alc = 5.97). [3H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist---a novel type of functional allosteric interaction.

0022-3565/02/3012-0720$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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