Jin_2014_Mol.Pharmacol_85_11

Heteropentameric neuronal nicotinic receptors assemble so that the canonical acetylcholine-binding sites are located at the interfaces between two pairs of subunits, while the fifth subunit does not participate in a canonical transmitter-binding site. Several subunits are considered to be unable to participate in forming a functional receptor when they occupy a position that would contribute to such a site, including the alpha5 subunit. The alpha5 subunit is of interest because of its apparent involvement in nicotine dependence and in the control of dopamine release. We have examined this question using alpha4 and beta2 subunits in concatemeric constructs with the alpha5 subunit, expressed in Xenopus oocytes. Using dimeric constructs of alpha4 and beta2 subunits expressed with free alpha5 and pentameric constructs incorporating a single copy of alpha5, we find that the alpha5 subunit can occupy the position of a nonbinding subunit, or replace a beta2 subunit participating in a canonical binding site. The resulting receptors functionally resemble pentamers assembled with two copies of alpha4 and three copies of beta2. Functional receptors apparently cannot be formed with alpha5 subunits in both canonical binding sites. These observations extend the present ideas on the possible positions in the pentamer that may be occupied by the alpha5 subunit, and suggest that additional physiologic or pharmacological subtypes of neuronal nicotinic receptors may be present in neurons.