title: Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes.
abstract: Human neuronal nicotinic acetylcholine receptors (nAChRs) h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 were expressed in Xenopus oocytes and tested for their sensitivities to the nicotinic agonists acetylcholine (ACh), nicotine, cytisine (CYT) and 1,1-dimethyl-4-phenylpiperazinium (DMPP) and the nAChR. antagonists mecamylamine (MEC), d-tubocurarine and dihydro-beta-erythroidine. CYT was the least efficacious agonist at hnAChRs containing beta 2 subunits, but it displayed significant activity at h alpha 2 beta 4, h alpha 3 beta 4, h alpha 4 beta 4 and h alpha 7 nAChRs. ACh was one of the most efficacious agonists at all hnAChRs, except at h alpha 3 beta 2, where DMPP was markedly more efficacious than ACh. ACh was among the least potent agonists at all hnAChRs. The rank order of potency displayed by h alpha 3 beta 2 and h alpha 3 beta 4 nAChRs (DMPP approximately CYT approximately nicotine > ACh and DMPP > CYT approximately nicotine > ACh, respectively), differs from that reported for their rat homologs (Luetje and Patrick, 1991; Covernton et al., 1994). The agonist profile observed in h alpha 7 also differs from that reported for its rat homolog (Seguela et al., 1993). Human alpha 4 beta 2 and h alpha 4 beta 4 nAChRs were more sensitive to dihydro-beta-erythroidine than d-tubocurarine, whereas h alpha 7 and h alpha 3 beta 4 were more sensitive to d-tubocurarine than dihydro-beta-erythroidine. These antagonists were equipotent at h alpha 2 beta 2, h alpha 3 beta 2 and h alpha 2 beta 4 nAChRs. MEC (3 microM) inhibited h alpha 2 beta 4 and h alpha 4 beta 4 nAChRs by > 80%, whereas h alpha 2 beta 2, h alpha 4 beta 2 and h alpha 7 nAChRs were inhibited by approximately 50%. Taken together, the differential sensitivities observed at various recombinant hnAChR subtypes indicate that both alpha and beta subunits contribute to the pharmacology of these ligand-gated channels. The unique selectivity profiles displayed by human nAChRs constitute a valuable tool for the development of selective nicotinic analogs as potential therapeutic drugs.
authors.affiliation: SIBIA Neurosciences, Inc., La Jolla, California, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Chavez-Noriega
authors.forename: J H
authors.initials: JH
authors.lastname: Crona
authors.forename: M S
authors.initials: MS
authors.lastname: Washburn
authors.forename: A
authors.initials: A
authors.lastname: Urrutia
authors.forename: K J
authors.initials: KJ
authors.lastname: Elliott
authors.forename: E C
authors.initials: EC
authors.lastname: Johnson
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000145:classification / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins