Rapid relief of block by mecamylamine of neuronal nicotinic acetylcholine receptors of rat chromaffin cells in vitro: An electrophysiological and modeling study

The mechanism responsible for the blocking action of mecamylamine on neuron al nicotinic acetylcholine receptors (nAChRs) was studied on rat isolated c hromaffin cells recorded under whole-cell patch clamp. Mecamylamine strongl y depressed (IC50 = 0.34 mu M) inward currents elicited by short pulses of nicotine, an effect slowly reversible on wash. The mecamylamine block was v oltage-dependent and promptly relieved by a protocol combining membrane dep olarization with a nicotine pulse. Either depolarization or nicotine pulses were insufficient per se to elicit block relief. Block relief was transien t; response depression returned in a use-dependent manner. Exposure to meca mylamine failed to block nAChRs if they were not activated by nicotine or i f they were activated at positive membrane potentials. These data suggest t hat mecamylamine could not interact with receptors either at rest or at dep olarized level. Other nicotinic antagonists like dihydro-beta-erythroidine or tubocurarine did not share this action of mecamylamine although proadife n partly mimicked it. Mecamylamine is suggested to penetrate and block open nAChRs that would subsequently close and trap this antagonist. Computer mo deling indicated that the mechanism of mecamylamine blocking action could b e described by assuming that 1) mecamylamine-blocked receptors possessed a much slower, voltage-dependent isomerization rate, 2) the rate constant for mecamylamine unbinding was large and poorly voltage dependent. Hence, chan nel reopening plus depolarization allowed mecamylamine escape and block rel ief. In the presence of mecamylamine, therefore, nAChRs acquire the new pro perty of operating as coincidence detectors for concomitant changes in memb rane potential and receptor occupancy.