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Vol. 53, Issue 3, 555-563, March 1998
4
2 Neuronal Nicotinic
Acetylcholine Receptor
Department of Physiology, Faculty of Medicine, University of
Geneva, CH-1211 Geneva 4, Switzerland
To extend our knowledge of the pharmacological profile of human
4
2 neuronal nicotinic receptors, we investigated the action of
hexamethonium on the major brain human nicotinic acetylcholine receptor
(nAChR) stably expressed in human embryonic kidney 293 cells. This
compound displays all of the characteristics of an open-channel blocker
at the human 42 nAChR: a voltage-dependent inhibition (more
pronounced at hyperpolarized potentials), absence of competition, and
use dependence. Moreover, we observed that classic
N-methyl-D-aspartate open-channel blockers
amantadine, 3,5-dimethyl-1-adamantanamine (memantine), and dizocilpine
[(+)-MK-801] and the calcium channel antagonist
8-(diethylamino)octyl-3,4,5-trimethoxybenzoate are powerful inhibitors
of the human 42 nAChR. Dose-inhibition curves yield, at 
100 mV,
IC50 values in the micromolar range for all of compounds
and Hill coefficients below unity. Whole-cell current-voltage
relationships display a strong rectification profile at hyperpolarized
potentials, and current blockades are fitted adequately by a
mathematical model that describes the mechanism of an ion channel
block. We conclude that these molecules are powerful human 42
open-channel blockers ranking in the following order of potency:
amantadine > memantine = hexamethonium > 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate ~ (+)-MK-801.
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