| Elucidating the molecular basis of action of a classic drug: guanidine compounds as inhibitors of voltage-gated potassium channels. | |
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MedLine Citation:
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PMID: 21926190 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Guanidine and its alkyl analogs stimulate the neuromuscular junction presynaptically by inhibiting voltage-gated potassium (Kv) channels, leading to enhanced release of acetylcholine in the synaptic cleft. This stimulatory effect of guanidine underlies its use in the therapy for the neuromuscular diseases myasthenic syndrome of Lambert-Eaton and botulism. The therapeutic use of guanidine is limited, however, because of side effects that accompany its administration. Therefore, the design of guanidine analogs with improved therapeutic indices is desirable. Progress toward this goal is hindered by the lack of knowledge of the mechanism by which these molecules inhibit Kv channels. Here we examine an array of possible mechanisms, including charge screening, disruption of the protein-lipid interfaces, direct interaction with the voltage sensors, and pore-binding. Our results demonstrate that guanidines bind within the intracellular pore of the channel and perturb a hydrophobic subunit interface to stabilize a closed state of the channel. This mechanism provides a foundation for the design of guanidine analogs for the therapeutic intervention of neuromuscular diseases. |
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Authors:
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Jeet Kalia; Kenton J Swartz |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural Date: 2011-09-16 |
Journal Detail:
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Title: Molecular pharmacology Volume: 80 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-11-21 Completed Date: 2012-01-12 Revised Date: 2013-05-23 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 1085-95 Citation Subset: IM |
Affiliation:
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Porter Neuroscience Research Center, Molecular Physiology and Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Female Guanidine / metabolism, pharmacology* Potassium Channel Blockers / metabolism, pharmacology* Potassium Channels, Voltage-Gated / antagonists & inhibitors, metabolism Protein Binding / physiology Shaker Superfamily of Potassium Channels / antagonists & inhibitors*, metabolism Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Potassium Channel Blockers; 0/Potassium Channels, Voltage-Gated; 0/Shaker Superfamily of Potassium Channels; 113-00-8/Guanidine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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