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Molecular Pharmacology

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Research ArticleArticle

Ligand Binding and Activation of Rat Nicotinic α4β2 Receptors Stably Expressed in HEK293 Cells

Kimberley Sabey, Ken Paradiso, Jessie Zhang and Joe Henry Steinbach
Molecular Pharmacology January 1999, 55 (1) 58-66; DOI: https://doi.org/10.1124/mol.55.1.58
Kimberley Sabey
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri
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Ken Paradiso
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri
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Jessie Zhang
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri
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Joe Henry Steinbach
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri
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Abstract

HEK293 cells were stably transfected with rat neuronal nicotinic α4 and β2 subunits. Binding of tritiated cytisine and nicotine to cell homogenates revealed the presence of a single class of high-affinity sites (dissociation constants 0.1 nM and 0.4 nM, respectively). Activation of nicotinic receptors was studied using whole-cell patch clamp methods, and acetylcholine, nicotine, dimethylphenylpiperazinium, and cytisine all produced a conductance increase. Responses desensitized to prolonged applications, at both positive and negative membrane potentials. The conductance was strongly rectifying, and outward currents were essentially absent. Responses were maximal at about 2 mM external calcium ion concentration and were reduced by about one-half at either nominally 0 or 10 mM external calcium. Di-hydro-β-erythroidine blocked physiological responses to acetylcholine and nicotine (IC50, 2.5 nM), and reduced cytisine binding in a competitive manner (K i20 nM). Physostigmine enhanced the response to low concentrations of acetylcholine or nicotine. The anesthetic steroid (+)-3α-hydroxy-5α-androstane-17β-carbonitrile blocked responses to acetylcholine (IC50, 1.3 μM), but had no effect on cytisine binding at a concentration of 30 μM. The binding properties of the receptors are those expected for rat neuronal nicotinic receptors composed of α4 and β2 subunits. The pharmacological properties indicate that the responsiveness of the receptors may be allosterically enhanced or inhibited.

Footnotes

    • Received July 31, 1998.
    • Accepted September 30, 1998.
  • Send reprint requests to: Dr. Joe Henry Steinbach, Department of Anesthesiology-8054, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mailjhs{at}morpheus.wustl.edu

  • This research was supported by National Institutes of Health grants R01 NS22356 and P01 GM47969 to J.H.S.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (1)
Molecular Pharmacology
Vol. 55, Issue 1
1 Jan 1999
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Research ArticleArticle

Ligand Binding and Activation of Rat Nicotinic α4β2 Receptors Stably Expressed in HEK293 Cells

Kimberley Sabey, Ken Paradiso, Jessie Zhang and Joe Henry Steinbach
Molecular Pharmacology January 1, 1999, 55 (1) 58-66; DOI: https://doi.org/10.1124/mol.55.1.58

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Research ArticleArticle

Ligand Binding and Activation of Rat Nicotinic α4β2 Receptors Stably Expressed in HEK293 Cells

Kimberley Sabey, Ken Paradiso, Jessie Zhang and Joe Henry Steinbach
Molecular Pharmacology January 1, 1999, 55 (1) 58-66; DOI: https://doi.org/10.1124/mol.55.1.58
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