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A Perturbed pK_a at the Binding Site of the Nicotinic Acetylcholine Receptor: Implications for Nicotine Binding

Petersson, E. James and Choi, Anita and Dahan, David S. and Lester, Henry A. and Dougherty, Dennis A. (2002) A Perturbed pK_a at the Binding Site of the Nicotinic Acetylcholine Receptor: Implications for Nicotine Binding. Journal of the American Chemical Society, 124 (43). pp. 12662-12663. ISSN 0002-7863. doi:10.1021/ja028206i.

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A series of tethered quaternary ammonium derivatives of Tyr have been incorporated into the binding site of the nicotinic acetylcholine receptor (nAChR) using the in vivo nonsense suppression method, producing constitutively active (self-gating) receptors. We have incorporated primary, secondary, and tertiary amine tethered agonists to give receptors whose constitutive activity can be modulated by pH. Lowering the pH protonates the tethered amine, giving it a positive charge and allowing it to reversibly activate the receptor. Tertiary and secondary tethered amines, TyrO3T and TyrO3S, have been successfully incorporated at α149 in the nAChR. Constitutive currents at pH 5.5 are 6 times those at pH 9.0. The pK_a of TyrO3T in the binding site appears to be 6 or lower, differing substantially from its pK_a in solution (∼9.3). This local pK_a perturbation has substantial implications for pharmacological research on the nAChR:  of the tertiary agonists considered, noracetylcholine experiences this pK_a perturbation, while nicotine does not.

Item Type:Article
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URLURL TypeDescription Information
Petersson, E. James0000-0003-3854-9210
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2002 American Chemical Society. Received 19 August 2002. Published online 5 October 2002. Published in print 1 October 2002. We thank Dr. Lintong Li for her help. This work was supported by the National Institutes of Health (NS-34407 and NS-11756).
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Issue or Number:43
Record Number:CaltechAUTHORS:20170414-144546207
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Official Citation:A Perturbed pKa at the Binding Site of the Nicotinic Acetylcholine Receptor:  Implications for Nicotine Binding E. James Petersson, Anita Choi, David S. Dahan, Henry A. Lester, and Dennis A. Dougherty Journal of the American Chemical Society 2002 124 (43), 12662-12663 DOI: 10.1021/ja028206i
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76579
Deposited By: Ruth Sustaita
Deposited On:14 Apr 2017 22:29
Last Modified:15 Nov 2021 17:01

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