The actions of muscle relaxants at nicotinic acetylcholine receptor isoforms

Garland, C.M., Foreman, R.C., Chad, J.E., Holden-Dye, L. and Walker, R.J. (1998) The actions of muscle relaxants at nicotinic acetylcholine receptor isoforms. European Journal of Pharmacology, 357 (1), 83-92. (doi:10.1016/S0014-2999(98)00542-1).

Abstract

The pharmacological diversity of the different isoforms of the nicotinic acetylcholine receptor arises from the diversity of the subunits that assemble to form the native receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic acetylcholine receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for ?, ?, ?, ? subunits (the native foetal muscle subunit combination), or with cRNAs for ?, ?, , ? subunits (the native adult muscle subunit combination), or with cRNAs for ?4?2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 ?M, respectively). At all three receptor types, d-tubocurarine and pancuronium blocked the responses elicited by acetylcholine in a reversible manner. Furthermore, the inhibition of the acetylcholine currents for the foetal and adult nicotinic acetylcholine receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range ?100 to ?40 mV. In oocytes expressing the foetal muscle nicotinic acetylcholine receptors the inhibition of the current in response to 100 ?M acetylcholine by 10 nM d-tubocurarine was 29±5% (mean±S.E.M.; n=7), and the inhibition by 10 nM pancuronium was 39±6% (mean±S.E.M.; n=8; P>0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic acetylcholine receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 ?M acetylcholine compared to the foetal muscle nicotinic acetylcholine receptor, with values of 55±5% (P<0.01; n=12) and 60±4% (P<0.001; n=10), respectively. Thus the developmental switch from the ? to the subunit alters the antagonism of the nicotinic acetylcholine receptor for both pancuronium and d-tubocurarine. Vecuronium was more potent than pancuronium. One nM vecuronium reduced the response to 100 ?M acetylcholine by 71±6% (n=10) for foetal and 63±5% (n=4) for adult nicotinic acetylcholine receptors. In the ?4?2 neuronal nicotinic acetylcholine receptor combination, 10 nM pancuronium was a more effective antagonist of the response to 100 ?M acetylcholine (69±6%, n=6) than 10 nM d-tubocurarine (30±5%; n=6; P<0.05 compared to pancuronium). This is in contrast to the adult muscle nicotinic acetylcholine receptor, where pancuronium and d-tubocurarine were equieffective. The expression of the ?2 subunit with muscle ?, and ? subunits formed a functional receptor which was blocked by pancuronium and d-tubocurarine in a similar manner to the ??1? subunit consistent with the hypothesis that the ? subunit is not a major determinant in the action of this drug at the adult muscle nicotinic acetylcholine receptor.

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Contributors

Author: J.E. Chad

Author: L. Holden-Dye

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