alpha 7 and beta 2 Nicotinic Acetylcholine Receptor Subunits Form Heteromeric Receptor Complexes that Are Expressed in the Human Cortex and Display Distinct Pharmacological Properties

作者：Thomsen Morten Skott; Zwart Ruud; Ursu Daniel; Jensen Majbrit Myrup; Pinborg Lars Hageman; Gilmour Gary; Wu Jie; Sher Emanuele; Mikkelsen Jens Damsgaard

来源：PLos One, 2015, 10(6): e0130572.

DOI：10.1371/journal.pone.0130572

The existence of alpha 7 beta 2 nicotinic acetylcholine receptors (nAChRs) has recently been demonstrated in both the rodent and human brain. Since alpha 7-containing nAChRs are promising drug targets for schizophrenia and Alzheimer's disease, it is critical to determine whether alpha 7 beta 2 nAChRs are present in the human brain, in which brain areas, and whether they differ functionally from alpha 7 nAChR homomers. We used alpha-bungarotoxin to affinity purify alpha 7-containing nAChRs from surgically excised human temporal cortex, and found that alpha 7 subunits co-purify with beta 2 subunits, indicating the presence of alpha 7 beta 2 nAChRs in the human brain. We validated these results by demonstrating co-purification of beta 2 from wild-type, but not alpha 7 or beta 2 knock-out mice. The pharmacology and kinetics of human alpha 7 beta 2 nAChRs differed significantly from that of alpha 7 homomers in response to nAChR agonists when expressed in Xenopus oocytes and HEK293 cells. Notably, alpha 7 beta 2 heteromers expressed in HEK293 cells display markedly slower rise and decay phases. These results demonstrate that alpha 7 subunits in the human brain form heteromeric complexes with beta 2 subunits, and that human alpha 7 beta 2 nAChR heteromers respond to nAChR agonists with a unique pharmacology and kinetic profile. alpha 7 beta 2 nAChRs thus represent an alternative mechanism for the reported clinical efficacy of alpha 7 nAChR ligands.

• 出版日期2015-6-18