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A photoisomerizable muscarinic antagonist. Studies of binding and of conductance relaxations in frog heart

Nargeot, Joel and Lester, Henry A. and Birdsall, Nigel J. M. and Stockton, Jane and Wassermann, Norbert H. and Erlanger, Bernard F. (1982) A photoisomerizable muscarinic antagonist. Studies of binding and of conductance relaxations in frog heart. Journal of General Physiology, 79 (4). pp. 657-678. ISSN 0022-1295. PMCID PMC2215484. http://resolver.caltech.edu/CaltechAUTHORS:NARjgp82

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Abstract

These experiments employ the photoisomerizable compound, 3,3'-bis- [alpha-(trimethylammonium)methyl]azobenzene (Bis-Q), to study the response to muscarinic agents in frog myocardium. In homogenates from the heart, trans-Bis-Q blocks the binding of [3H]-N-methylscopolamine to muscarinic receptors. In voltage-clamped atrial trabeculae, trans- Bis-Q blocks the agonist-induced potassium conductance. The equilibrium dose-response curve for carbachol is shifted to the right, suggesting competitive blockade. Both the biochemical and electrophysiological data yield a dissociation constant of 4-5 microM for trans-Bis-Q; the cis configuration is severalfold less potent as a muscarinic blocker. Voltage-clamped preparations were exposed simultaneously to carbachol and Bis-Q and were subjected to appropriately filtered flashes (less than 1 ms duration) from a xenon flashlamp. Trans leads to cis and cis leads to trans photoisomerizations cause small (less than 20%) increases and decreases, respectively, in the agonist-induced current. The relaxation follows an S-shaped time course, including an initial delay or period of zero slope. The entire waveform is described by [1 - exp(-kt)]n. At 23 degrees C, k is approximately 3 s-1 and n is 2. Neither k nor n is affected when: (a) [Bis-Q] is varied between 5 and 100 microM; (b) [carbachol] is varied between 1 and 50 microM; (c) carbachol is replaced by other agonists (muscarine, acetylcholine, or acetyl-beta-methylcholine); or (d) the voltage is varied between the normal resting potential and a depolarization of 80 mV. However, in the range of 13-30 degrees C, k increases with temperature; the Q10 is between 2 and 2.5. In the same range, n does not change significantly. Like other investigators, we conclude that the activation kinetics of the muscarinic K+ conductance are not determined by ligand-receptor binding, but rather by a subsequent sequence of two (or more) steps with a high activation energy.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://jgp.rupress.org/cgi/content/abstract/79/4/657PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2215484/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1982 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 17 April 1981 and in revised form 12 September 1981. Supported by Research Career Development Award NS-272 to H.A.L. and grants NS-11756 and NS-15581 from the National Institutes of Health, a NATO fellowship to J.N., grant 78.7.2582 from the Délégation Générale à la Recherche Scientifique et Technique, the Pew Foundation, the Muscular Dystrophy Association, and grant PCM-77-19280 from the National Science Foundation.
Funders:
Funding AgencyGrant Number
NIHNS-272
NIHNS-11756
NIHNS-15581
North Atlantic Treaty Organization (NATO)UNSPECIFIED
Délégation Générale à la Recherche Scientifique et TechniqueUNSPECIFIED
Pew FoundationUNSPECIFIED
Muscular Dystrophy AssociationUNSPECIFIED
NSFPCM-77-19280
PubMed Central ID:PMC2215484
Record Number:CaltechAUTHORS:NARjgp82
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:NARjgp82
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:12039
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:21 Oct 2008 04:03
Last Modified:09 Nov 2017 00:16

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