ALPHA-5 SUBUNIT ALTERS DESENSITIZATION, PHARMACOLOGY, CA-3 NICOTINIC RECEPTORS(+ PERMEABILITY AND CA++ MODULATION OF HUMAN NEURONAL ALPHA)

Functional effects of human alpha 5 nicotinic ACh receptor (AChR) subu nits coassembled with alpha 3 and beta 2 or with alpha 3 and beta 4 su bunits, were investigated in Xenopus oocytes. The presence of alpha 5 subunits altered some properties of both alpha 3 AChRs and differentia lly altered other properties of alpha 3 beta 2 AChRs vs. alpha 3 beta 4 AChRs. alpha 5 subunits increased desensitization and Ca++ permeabil ity of all alpha 3 AChRs. The Ca++ permeabilities of both alpha 3 beta 2 alpha 5 and alpha 3 beta 4 alpha 5 AChRs were comparable to that of alpha 7 AChRs. As we have shown previously, alpha 5 subunits increase d the ACh sensitivity of alpha 3 beta 2 AChRs 50-fold but had little e ffect on alpha 3 beta 4 AChRs. alpha 5 caused only subtle changes in t he activation potencies of alpha 3 AChRs for nicotine, cytisine and 1, 1-dimethyl-4-plenylpiperazinium (DMPP). However, alpha 5 increased the efficacies of nicotine and DMPP on alpha 3 beta 2 AChRs but decreased them on alpha 3 beta 4 AChRs. Immunoisolation of cloned human AChRs e xpressed in oocytes showed that alpha 5 efficiently coassembled with a lpha 3 plus beta 2 and/or beta 4 subunits. As expected, human AChRs im munoisolated from SH-SY5Y neuroblastoma cells showed that AChRs contai ning alpha 3 and probably alpha 5 subunits were present, but alpha 4 A ChRs were not. In brain, by contrast, alpha 4 beta 2 AChRs were shown to predominate over alpha 3 AChRs. Some of the brain alpha 4 beta 2 AC hRs were found to contain alpha 5 subunits.