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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Pharmacological Characterization of Recombinant Human Neuronal Nicotinic Acetylcholine Receptors hα2β2, hα2β4, hα3β2, hα3β4, hα4β2, hα4β4 and hα7 Expressed in Xenopus Oocytes

Laura E. Chavez-Noriega, James H. Crona, Mark S. Washburn, Arturo Urrutia, Kathryn J. Elliott and Edwin C. Johnson
Journal of Pharmacology and Experimental Therapeutics January 1997, 280 (1) 346-356;
Laura E. Chavez-Noriega
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James H. Crona
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Mark S. Washburn
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Arturo Urrutia
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Kathryn J. Elliott
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Edwin C. Johnson
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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.

Footnotes

  • Send reprint requests to: Dr. Laura E. Chavez-Noriega, SIBIA Neurosciences, Inc., 505 Coast Boulevard South, Suite 300, La Jolla, CA 92037.

  • Abbreviations:
    nAChR
    neuronal nicotinic acetylcholine receptors
    ACh
    acetylcholine
    NIC
    (-)nicotine
    CYT
    cytisine
    DMPP
    1,1-dimethyl-4-phenylpiperazinium
    MEC
    mecamylamine
    d-Tubo
    d-tubocurarine
    DHβE
    dihydro-β-erythroidine
    DRCs
    dose-response curves
    HEPES
    N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]
    • Received April 12, 1996.
    • Accepted September 5, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 1
1 Jan 1997
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Pharmacological Characterization of Recombinant Human Neuronal Nicotinic Acetylcholine Receptors hα2β2, hα2β4, hα3β2, hα3β4, hα4β2, hα4β4 and hα7 Expressed in Xenopus Oocytes
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Pharmacological Characterization of Recombinant Human Neuronal Nicotinic Acetylcholine Receptors hα2β2, hα2β4, hα3β2, hα3β4, hα4β2, hα4β4 and hα7 Expressed in Xenopus Oocytes

Laura E. Chavez-Noriega, James H. Crona, Mark S. Washburn, Arturo Urrutia, Kathryn J. Elliott and Edwin C. Johnson
Journal of Pharmacology and Experimental Therapeutics January 1, 1997, 280 (1) 346-356;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Pharmacological Characterization of Recombinant Human Neuronal Nicotinic Acetylcholine Receptors hα2β2, hα2β4, hα3β2, hα3β4, hα4β2, hα4β4 and hα7 Expressed in Xenopus Oocytes

Laura E. Chavez-Noriega, James H. Crona, Mark S. Washburn, Arturo Urrutia, Kathryn J. Elliott and Edwin C. Johnson
Journal of Pharmacology and Experimental Therapeutics January 1, 1997, 280 (1) 346-356;
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