The existence of Î±7Î²2 nicotinic acetylcholine receptors (nAChRs) has recently been demonstrated in both the rodent and human brain. Since Î±7-containing nAChRs are promising drug targets for schizophrenia and Alzheimer's disease, it is critical to determine whether Î±7Î²2 nAChRs are present in the human brain, in which brain areas, and whether they differ functionally from Î±7 nAChR homomers. We used Î±-bungarotoxin to affinity purify Î±7-containing nAChRs from surgically excised human temporal cortex, and found that Î±7 subunits co-purify with Î²2 subunits, indicating the presence of Î±7Î²2 nAChRs in the human brain. We validated these results by demonstrating co-purification of Î²2 from wild-type, but not Î±7 or Î²2 knock-out mice. The pharmacology and kinetics of human Î±7Î²2 nAChRs differed significantly from that of Î±7 homomers in response to nAChR agonists when expressed in Xenopus oocytes and HEK293 cells. Notably, Î±7Î²2 heteromers expressed in HEK293 cells display markedly slower rise and decay phases. These results demonstrate that Î±7 subunits in the human brain form heteromeric complexes with Î²2 subunits, and that human Î±7Î²2 nAChR heteromers respond to nAChR agonists with a unique pharmacology and kinetic profile. Î±7Î²2 nAChRs thus represent an alternative mechanism for the reported clinical efficacy of Î±7 nAChR ligands.
Digital Object Identifier (DOI)
Thomsen, Morten Skott; Zwart, Ruud; Ursu, Daniel; Jensen, Majbrit Myrup; Pinborg, Lars Hageman; Gilmour, Gary; Wu, Jie; Sher, Emanuele; and Mikkelsen, Jens Damsgaard, "Î±7 And Î²2 Nicotinic Acetylcholine Receptor Subunits Form Heteromeric Receptor Complexes That Are Expressed In The Human Cortex And Display Distinct Pharmacological Properties" (2015). Translational Neuroscience. 438.