Modeling study of mecamylamine block of muscle type acetylcholine receptors

Abstract

The blocking action of mecamylamine on different types of nicotinic acetylcholine receptors (nAChRs) has been extensively studied and used as a tool to characterize the nAChRs from different synapses. However, mechanism of mecamylamine action was not fully explored for all types of nAChRs. In the present study, we provide brief description of the mecamylamine action on muscle nAChRs expressed at the frog neuromuscular junction. In this preparation mecamylamine block of nAChRs was accompanied by a use-dependent block relief induced by membrane depolarization combined with the activation of nAChRs by endogenous agonist acetylcholine (ACh). Further, three kinetic models of possible mecamylamine interaction with nAChRs were analyzed including simple open channel block, symmetrical trapping block and asymmetrical trapping block. This analysis suggested that mecamylamine action could be described on the basis of trapping mechanism, when the antagonist remained inside the channel even in the absence of bound agonist. Such receptors with trapped mecamylamine inside were predicted to have a closing rate constant about three times faster than resting one and a fast voltage-dependent unblocking rate constant. Specific experimental conditions and morphological organization of the neuromuscular synapses were considered to simulate time course of the mecamylamine block development. Thus, likewise for the neuronal nAChRs, the trapping mechanism determined the action of mecamylamine on synaptic neuromuscular currents evoked by the endogenous agonist acetylcholine (ACh), however specific morphological organization of the synaptic transmission delayed time development of the currents block.

Acetylcholine-Induced Inhibition of Presynaptic Calcium Signals and Transmitter Release in the Frog Neuromuscular Junction

“…Mecamylamine is able to block various subtypes of nicotinic receptors depending on concentration within the range from 640 nM to 6.9 μM (Papke et al, 2001; Rabenstein et al, 2006; Ostroumov et al, 2008). Next, we tested the effects of different concentrations of mecamylamine.…”

The biological significance of substrate inhibition: A mechanism with diverse functions

“…Figure 4A shows the results of some simple model calculations. The black curve is the rate of input of ACH into the cleft, consistent with known rapid input [33,35]. Typical apparent K m values are in the range 50-100 mM [28,36,37]; we used the value 58 mM in the model [28].…”

“…The peak of the ACHe velocity curve occurs at about 1 mM [28]. The rise time of ACH release is less than 100 ms [26,33], and the concentration of ACH is quickly driven past 1 mM and rises to 10 mM and perhaps higher [32]. This is possible because of the very high concentration of ACH in presynaptic vesicles, approximately 1 M [34].…”

Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

“…Another class of noncompetitive antagonists is comprised of drugs which bind specifically to activated receptors, usually by binding to the open channel itself. This form of inhibition is usually use-dependent and so produces the greatest inhibition when the stimulation of the receptor is greatest [184].…”