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A covalently bound photoisomerizable agonist. Comparison with reversibly bound agonists at electrophorus electroplaques

Lester, Henry A. and Krouse, Mauri E. and Nass, Menasche M. and Wassermann, Norbert H. and Erlanger, Bernard F. (1980) A covalently bound photoisomerizable agonist. Comparison with reversibly bound agonists at electrophorus electroplaques. Journal of General Physiology, 75 (2). pp. 207-232. ISSN 0022-1295. http://resolver.caltech.edu/CaltechAUTHORS:LESjgp80

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Abstract

After disulphide bonds are reduced with dithiothreitol, trans-3-(alpha-bromomethyl)-3’-[alpha-(trimethylammonium)methyl]azobenzene (trans-QBr) alkylates a sulfhydryl group on receptors. The membrane conductance induced by this “tethered agonist” shares many properties with that induced by reversible agonists. Equilibrium conductance increases as the membrane potential is made more negative; the voltage sensitivity resembles that seen with 50 [mu]M carbachol. Voltage- jump relaxations follow an exponential time-course; the rate constants are about twice as large as those seen with 50 mu M carbachol and have the same voltage and temperature sensitivity. With reversible agonists, the rate of channel opening increases with the frequency of agonist-receptor collisions: with tethered trans-Qbr, this rate depends only on intramolecular events. In comparison to the conductance induced by reversible agonists, the QBr-induced conductance is at least 10-fold less sensitive to competitive blockade by tubocurarine and roughly as sensitive to “open-channel blockade” bu QX-222. Light-flash experiments with tethered QBr resemble those with the reversible photoisomerizable agonist, 3,3’,bis-[alpha-(trimethylammonium)methyl]azobenzene (Bis-Q): the conductance is increased by cis {arrow} trans photoisomerizations and decreased by trans {arrow} cis photoisomerizations. As with Bis-Q, ligh-flash relaxations have the same rate constant as voltage-jump relaxations. Receptors with tethered trans isomer. By comparing the agonist-induced conductance with the cis/tans ratio, we conclude that each channel’s activation is determined by the configuration of a single tethered QBr molecule. The QBr-induced conductance shows slow decreases (time constant, several hundred milliseconds), which can be partially reversed by flashes. The similarities suggest that the same rate-limiting step governs the opening and closing of channels for both reversible and tethered agonists. Therefore, this step is probably not the initial encounter between agonist and receptor molecules.


Item Type:Article
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http://www.jgp.org/cgi/content/abstract/75/2/207PublisherUNSPECIFIED
Additional Information:Copyright © 1980 by The Rockefeller University Press. RUP grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode. Received for publication 18 June 1979. We thank D. Williams for assisting with the animals and dissecting the cells, J.M. Nerbonne and M.M. Weinstock for discussion, and Astra Pharmaceuticals, Inc., for a gift of QX-222. This work was supported by the Muscular Dystrophy Associations of America (postdoctoral fellowship to Dr. Nass and grant-in-aid), by the National Institutes of Health (Research Career Development Award NS-272 to Dr. Lester and grant NS-11756), and by the National Science Foundation (grant PCM-74-02140).
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Funding AgencyGrant Number
Muscular Dystrophy Associations of AmericaUNSPECIFIED
National Institutes of HealthNS-272
National Institutes of HealthNS-11756
National Science FoundationPCM-74-02140
Record Number:CaltechAUTHORS:LESjgp80
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:LESjgp80
Usage Policy:RUP grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode.
ID Code:11551
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:04 Sep 2008 06:00
Last Modified:26 Dec 2012 10:16

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