Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include α5 or α6 subunits and that mediate synaptosomal neurotransmitter release

Desensitization is a complex property of nicotinic acetylcholine receptors (nAChR). Several subtypes of nAChR have high sensitivity to nicotine and mediate effects of nicotine at concentrations found in blood of tobacco smokers. Desensitization of some of these receptor subtypes has been studied in model systems, however, other subtypes have been difficult to express heterologously in native forms. In addition, model systems may not have the same accessory molecules and post-translational modifications found in native populations. We have used wild-type and subunit null mutant mice to study desensitization properties of the high sensitivity alpha 4 beta 2-nAChRs including those that have alpha 5 subunits at both GABAergic and dopaminergic nerve terminals. In addition, we have studied the desensitization of one subtype of alpha 6 beta 2-nAChRs at dopaminergic terminals using alpha 4 subunit null mutant mice. Exposure to low nicotine concentrations, leads to rapid, but partial desensitization of activity mediated by these receptors. alpha 4 beta 2-nAChRs including alpha 5 subunits show faster rates of recovery from desensitization than alpha 4 beta 2-nAChRs without alpha 5. Inclusion of the (15 subunit significantly shifts the concentration response for desensitization to higher values, indicating that receptors with alpha 5 subunits are less desensitized by a 10-min exposure to low concentrations of nicotine. Receptors with alpha 6 subunits appear to desensitize to a lesser degree than those with alpha 4 subunits, indicating that alpha 6 beta 2-nAChRs are somewhat resistant to desensitization by nicotine. These results highlight the importance of studying various receptor subtypes in native systems and how they may differentially respond to nicotine and to nicotinic drugs. (C) 2011 Elsevier Ltd. All rights reserved.