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Vol. 280, Issue 1, 346-356, 1997
2
2, h24, h32,
h34, h42, h44 and h7 Expressed in
Xenopus Oocytes
SIBIA Neurosciences, Inc., La Jolla, California
Human neuronal nicotinic acetylcholine receptors (nAChRs) h
2
2,
h24, h32, h34, h42, h44 and h7 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--erythroidine. CYT was the least efficacious agonist at
hnAChRs containing 2 subunits, but it displayed significant activity
at h24, h34, h44 and h7 nAChRs. ACh was one
of the most efficacious agonists at all hnAChRs, except at h32, 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 h32 and h34 nAChRs (DMPP
CYTnicotine>ACh
and DMPP > CYTnicotine>ACh, respectively), differs from that
reported for their rat homologs (; ). The agonist profile observed in h7
also differs from that reported for its rat homolog (Seguela et
al., 1993). Human 42 and h44 nAChRs were more
sensitive to dihydro--erythroidine than d-tubocurarine, whereas
h7 and h34 were more sensitive to d-tubocurarine than
dihydro--erythroidine. These antagonists were equipotent at
h22, h32 and h24 nAChRs. MEC (3 µM) inhibited h24 and h44 nAChRs by > 80%, whereas h22,
h42 and h7 nAChRs were inhibited by approximately 50%. Taken
together, the differential sensitivities observed at various
recombinant hnAChR subtypes indicate that both and 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.
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