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

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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 β2 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 α-bungarotoxin, are not altered in β2 −/− mice, and contain the α7 subunit. Type 2 nAChRs contain the β2 subunit because they are absent in β2 −/− mice, bind all nicotinic agonists used with high affinity (excluding α-bungarotoxin), have an order of potency for nicotine ≫ cytisine in electrophysiological experiments, and are likely to be composed of α4β2 in most brain regions, with other α 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 β2 −/− mice strongly suggest a subunit composition of α3β4. Type 4 nAChRs bind cytisine and epibatidine with high affinity in equilibrium binding experiments and persist in β2 −/− 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 α subunits should allow a further dissection of nAChR subclasses.