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Research ArticleCELLULAR AND MOLECULAR

Identification of Residues That Confer α-Conotoxin-PnIA Sensitivity on the α3 Subunit of Neuronal Nicotinic Acetylcholine Receptors

Drew Everhart, Edward Reiller, Armen Mirzoian, J. Michael McIntosh, Arun Malhotra and Charles W. Luetje
Journal of Pharmacology and Experimental Therapeutics August 2003, 306 (2) 664-670; DOI: https://doi.org/10.1124/jpet.103.051656
Drew Everhart
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Edward Reiller
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Armen Mirzoian
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J. Michael McIntosh
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Arun Malhotra
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Charles W. Luetje
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Abstract

Neuronal nicotinic receptors composed of the α3 and β2 subunits are at least 1000-fold more sensitive to blockade by α-conotoxin-PnIA than are α2β2 receptors. A series of chimeric subunits, formed from portions of α2 and α3, were coexpressed with β2 in Xenopus oocytes and tested for toxin sensitivity. We found determinants of toxin sensitivity to be widely distributed in the extracellular domain of α3. Analysis of receptors formed by a series of mutant α3 subunits, in which residues that differ between α3 and α2 were changed from what occurs in α3 to what occurs in α2, allowed identification of three determinants of α-conotoxin-PnIA sensitivity: proline 182, isoleucine 188, and glutamine 198. Comparison with determinants of α-conotoxin-MII and κ-bungarotoxin sensitivity on the α3 subunit revealed overlapping, but distinct, arrays of determinants for each of these three toxins. When tested against an EC50 concentration of acetylcholine, the IC50 for α-conotoxin-PnIA blockade was 25 ± 4 nM for α3β2, 84 ± 7 nM for α3P182Tβ2, 700 ± 92 nM for α3I188Kβ2, and 870 ± 61 nM for α3Q198Pβ2. To examine the location of these residues within the receptor structure, we generated a homology model of the α3β2 receptor extracellular domain using the structure of the acetylcholine binding protein as a template. All three residues are located on the C-loop of the α3 subunit, with isoleucine 188 nearest the acetylcholine-binding pocket.

Footnotes

  • This work was supported by National Institutes of Health Grants DA08102 (to C.W.L.) and MH53631 (to J.M.M.). A.M. was supported in part by awards from the Florida Biomedical Research Foundation (BM030) and the American Heart Association, Florida/Puerto Rico Affiliate (SDG-0130456B). D.E. was supported in part by T32-HL07188.

  • DOI: 10.1124/jpet.103.051656.

  • ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; AChBP, acetylcholine binding protein; ACh, acetylcholine; BSA, bovine serum albumin; MII, α-conotoxin-MII; PnIA, α-conotoxin-PnIA; κ-Bgt, κ-bungarotoxin.

  • ↵1 Current address: Cornell Veterinary School, Ithaca, NY 14853.

    • Received March 28, 2003.
    • Accepted May 5, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 2
1 Aug 2003
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Research ArticleCELLULAR AND MOLECULAR

Identification of Residues That Confer α-Conotoxin-PnIA Sensitivity on the α3 Subunit of Neuronal Nicotinic Acetylcholine Receptors

Drew Everhart, Edward Reiller, Armen Mirzoian, J. Michael McIntosh, Arun Malhotra and Charles W. Luetje
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 664-670; DOI: https://doi.org/10.1124/jpet.103.051656

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Research ArticleCELLULAR AND MOLECULAR

Identification of Residues That Confer α-Conotoxin-PnIA Sensitivity on the α3 Subunit of Neuronal Nicotinic Acetylcholine Receptors

Drew Everhart, Edward Reiller, Armen Mirzoian, J. Michael McIntosh, Arun Malhotra and Charles W. Luetje
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 664-670; DOI: https://doi.org/10.1124/jpet.103.051656
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