“Orphan” α6 Nicotinic AChR Subunit Can Form a Functional Heteromeric Acetylcholine Receptor

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Abstract
Previously, a rat brain cDNA was reported that was designated α6 because of its homology with nicotinic acetylcholine receptor (AChR) α subunits, being especially similar to α3, but no acetylcholine-gated cation channels were detected when it was expressed in Xenopus laevis oocytes alone or in combination with other known rat AChR subunits. We cloned chicken α6 and human β4 AChR subunits and tested for acetylcholine-gated cation channels with α6 by expression in X. laevis oocytes alone or in pairwise combination with chicken α3, β2, or β4 or with human α3, β2, or β4 AChR subunits. Chicken α6 formed detectable functional AChRs only when expressed together with the human β4 subunit. The α6β4 AChR-mediated currents show strong inward rectification and dependence on extracellular Ca2+. It exhibited a distinct pharmacological profile with an EC50value of 28 μm for acetylcholine, 24 nmfor (+)-epibatidine, 6.6 μm cytisine, and 15 μm 1,1-dimethyl-4-phenylpiperazinium. Both cytisine and 1,1-dimethyl-4-phenylpiperazinium behaved as partial (∼30%) agonists. Remarkably, nicotine (EC50 = 22 μm) was an even weaker partial agonist (∼18%) and had a relatively long-lasting inhibitory effect. Coexpression of the previously cloned rat α6 subunit with the human the β4 subunit also resulted in functional α6β4 AChRs with properties resembling those of the chicken/human α6β4 AChRs. Therefore, α6 can function as part of AChRs with unusual pharmacological properties.