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6 Nicotinic AChR Subunit Can Form a Functional
Heteromeric Acetylcholine Receptor
Departments of
Neuroscience (V.G., A.K., J.L.) and
Pharmacology
(R.A., J.L.), University of Pennsylvania Medical School, Philadelphia,
Pennsylvania, 19104-6074
Previously, a rat brain cDNA was reported that was designated 
6
because of its homology with nicotinic acetylcholine receptor (AChR)
subunits, being especially similar to 3, 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 6 and human 
4
AChR subunits and tested for acetylcholine-gated cation channels with
6 by expression in X. laevis oocytes alone or in
pairwise combination with chicken 3, 2, or 4 or with human
3, 2, or 4 AChR subunits. Chicken 6 formed detectable
functional AChRs only when expressed together with the human 4
subunit. The 64 AChR-mediated currents show strong inward
rectification and dependence on extracellular Ca2+. It
exhibited a distinct pharmacological profile with an EC50 value of 28 µM for acetylcholine, 24 nM
for (+)-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 6 subunit with the human the 4 subunit also resulted in
functional 64 AChRs with properties resembling those of the
chicken/human 64 AChRs. Therefore, 6 can function as part of
AChRs with unusual pharmacological properties.
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