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 α4β2-nAChRs including those that have α5 subunits at both GABAergic and dopaminergic nerve terminals. In addition, we have studied the desensitization of one subtype of α6β2-nAChRs at dopaminergic terminals using α4 subunit null mutant mice. Exposure to low nicotine concentrations, leads to rapid, but partial desensitization of activity mediated by these receptors. α4β2-nAChRs including α5 subunits show faster rates of recovery from desensitization than α4β2-nAChRs without α5. Inclusion of the α5 subunit significantly shifts the concentration response for desensitization to higher values, indicating that receptors with α5 subunits are less desensitized by a 10-min exposure to low concentrations of nicotine. Receptors with α6 subunits appear to desensitize to a lesser degree than those with α4 subunits, indicating that α6β2-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.