Modulation of Human Neuronal ␣3 Nicotinic Receptors 1

Abstract

ABSTRACT Functional effects of human ␣5 nicotinic ACh receptor (AChR) subunits coassembled with ␣3 and ␤2 or with ␣3 and ␤4 subunits, were investigated in Xenopus oocytes. The presence of ␣5 subunits altered some properties of both ␣3 AChRs and differentially altered other properties of ␣3␤2 AChRs vs. ␣3␤4 AChRs. ␣5 subunits increased desensitization and Ca ϩϩ permeability of all ␣3 AChRs. The Ca ϩϩ permeabilities of both ␣3␤2␣5 and ␣3␤4␣5 AChRs were comparable to that of ␣7 AChRs. As we have shown previously, ␣5 subunits increased the ACh sensitivity of ␣3␤2 AChRs 50-fold but had little effect on ␣3␤4 AChRs. ␣5 caused only subtle changes in the activation potencies of ␣3 AChRs for nicotine, cytisine and 1,1-dimethyl-4-plenylpiperazinium (DMPP). However, ␣5 increased the efficacies of nicotine and DMPP on ␣3␤2 AChRs but decreased them on ␣3␤4 AChRs. Immunoisolation of cloned human AChRs expressed in oocytes showed that ␣5 efficiently coassembled with ␣3 plus ␤2 and/or ␤4 subunits. As expected, human AChRs immunoisolated from SH-SY5Y neuroblastoma cells showed that AChRs containing ␣3 and probably ␣5 subunits were present, but ␣4 AChRs were not. In brain, by contrast, ␣4␤2 AChRs were shown to predominate over ␣3 AChRs. Some of the brain ␣4␤2 AChRs were found to contain ␣5 subunits. Neuronal nicotinic AChRs are thought to be formed by pentameric assemblies of certain combinations of ␣2, ␣3, ␣4, ␣5, ␣6, ␣7, ␣8, ␣9, ␤2, ␤3 and ␤4 subunits Our initial studies of human ␣5 subunits expressed in Xenopus oocytes showed that they assembled efficiently with human ␣3 and ␤2 or human ␣3 and ␤4 subunits to form AChRs that desensitized more rapidly and that, especially in the case of ␣3␤2␣5 AChRs, exhibited altered pharmacological propertie