Identification of Four Classes of Brain Nicotinic Receptors Using β2 Mutant Mice

Abstract

Although the expression patterns of the neuronal nicotinic acetylcholine receptor (nAChR) subunits thus far described are known, the subunit composition of functional receptors in different brain areas is an ongoing question. Mice lacking the beta2 subunit of the nAChR were used for receptor autoradiography studies and patch-clamp recording in thin brain slices. Four distinct types of nAChRs were identified, expanding on an existing classification [Alkondon M, Albuquerque EX (1993) Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes. J Pharmacol Exp Ther 265:1455-1473.], and tentatively identifying the subunit composition of nAChRs in different brain regions. Type 1 nAChRs bind alpha-bungarotoxin, are not altered in beta2 -/- mice, and contain the alpha7 subunit. Type 2 nAChRs contain the beta2 subunit because they are absent in beta2 -/- mice, bind all nicotinic agonists used with high affinity (excluding alpha-bungarotoxin), have an order of potency for nicotine >> cytisine in electrophysiological experiments, and are likely to be composed of alpha4 beta2 in most brain regions, with other alpha subunits contributing in specific areas. Type 3 nAChRs bind epibatidine with high affinity in equilibrium binding experiments and show that cytisine is as effective as nicotine in electrophysiological experiments; their distribution and persistence in beta2 -/- mice strongly suggest a subunit composition of alpha3 beta4. Type 4 nAChRs bind cytisine and epibatidine with high affinity in equilibrium binding experiments and persist in beta2 -/- mice; cytisine = nicotine in electrophysiological experiments. Type 4 nAChRs also exhibit faster desensitization than type 3 nAChRs at high doses of nicotine. Knock-out animals lacking individual alpha subunits should allow a further dissection of nAChR subclasses.