Abstract

Human neuronal nicotinic acetylcholine receptors (nAChRs) hα2β2, hα2β4, hα3β2, hα3β4, hα4β2, hα4β4 and hα7 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-β-erythroidine. CYT was the least efficacious agonist at hnAChRs containing β2 subunits, but it displayed significant activity at hα2β4, hα3β4, hα4β4 and hα7 nAChRs. ACh was one of the most efficacious agonists at all hnAChRs, except at hα3β2, 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 hα3β2 and hα3β4 nAChRs (DMPP≈CYT≈nicotine>ACh and DMPP > CYT≈nicotine>ACh, respectively), differs from that reported for their rat homologs (Luetje and Patrick, 1991; Coverntonet al., 1994). The agonist profile observed in hα7 also differs from that reported for its rat homolog (Seguela et al., 1993). Human α4β2 and hα4β4 nAChRs were more sensitive to dihydro-β-erythroidine than d-tubocurarine, whereas hα7 and hα3β4 were more sensitive to d-tubocurarine than dihydro-β-erythroidine. These antagonists were equipotent at hα2β2, hα3β2 and hα2β4 nAChRs. MEC (3 μM) inhibited hα2β4 and hα4β4 nAChRs by > 80%, whereas hα2β2, hα4β2 and hα7 nAChRs were inhibited by approximately 50%. Taken together, the differential sensitivities observed at various recombinant hnAChR subtypes indicate that both α and β 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.