title: α7 and β2 Nicotinic Acetylcholine Receptor Subunits Form Heteromeric Receptor Complexes that Are Expressed in the Human Cortex and Display Distinct Pharmacological Properties.
abstract: The existence of α7β2 nicotinic acetylcholine receptors (nAChRs) has recently been demonstrated in both the rodent and human brain. Since α7-containing nAChRs are promising drug targets for schizophrenia and Alzheimer's disease, it is critical to determine whether α7β2 nAChRs are present in the human brain, in which brain areas, and whether they differ functionally from α7 nAChR homomers. We used α-bungarotoxin to affinity purify α7-containing nAChRs from surgically excised human temporal cortex, and found that α7 subunits co-purify with β2 subunits, indicating the presence of α7β2 nAChRs in the human brain. We validated these results by demonstrating co-purification of β2 from wild-type, but not α7 or β2 knock-out mice. The pharmacology and kinetics of human α7β2 nAChRs differed significantly from that of α7 homomers in response to nAChR agonists when expressed in Xenopus oocytes and HEK293 cells. Notably, α7β2 heteromers expressed in HEK293 cells display markedly slower rise and decay phases. These results demonstrate that α7 subunits in the human brain form heteromeric complexes with β2 subunits, and that human α7β2 nAChR heteromers respond to nAChR agonists with a unique pharmacology and kinetic profile. α7β2 nAChRs thus represent an alternative mechanism for the reported clinical efficacy of α7 nAChR ligands.
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten Skøtt
authors.initials: MS
authors.lastname: Thomsen
authors.affiliation: Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, United Kingdom.
authors.forename: Ruud
authors.initials: R
authors.lastname: Zwart
authors.affiliation: Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ursu
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Majbrit Myrup
authors.initials: MM
authors.lastname: Jensen
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark; Epilepsy Clinic, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lars Hageman
authors.initials: LH
authors.lastname: Pinborg
authors.affiliation: Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.affiliation: Divisions of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, United Kingdom.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sher
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jens Damsgaard
authors.initials: JD
authors.lastname: Mikkelsen
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor