Thomsen_2015_PLoS.One_10_e0130572

The existence of alpha7beta2 nicotinic acetylcholine receptors (nAChRs) has recently been demonstrated in both the rodent and human brain. Since alpha7-containing nAChRs are promising drug targets for schizophrenia and Alzheimer's disease, it is critical to determine whether alpha7beta2 nAChRs are present in the human brain, in which brain areas, and whether they differ functionally from alpha7 nAChR homomers. We used alpha-bungarotoxin to affinity purify alpha7-containing nAChRs from surgically excised human temporal cortex, and found that alpha7 subunits co-purify with beta2 subunits, indicating the presence of alpha7beta2 nAChRs in the human brain. We validated these results by demonstrating co-purification of beta2 from wild-type, but not alpha7 or beta2 knock-out mice. The pharmacology and kinetics of human alpha7beta2 nAChRs differed significantly from that of alpha7 homomers in response to nAChR agonists when expressed in Xenopus oocytes and HEK293 cells. Notably, alpha7beta2 heteromers expressed in HEK293 cells display markedly slower rise and decay phases. These results demonstrate that alpha7 subunits in the human brain form heteromeric complexes with beta2 subunits, and that human alpha7beta2 nAChR heteromers respond to nAChR agonists with a unique pharmacology and kinetic profile. alpha7beta2 nAChRs thus represent an alternative mechanism for the reported clinical efficacy of alpha7 nAChR ligands.