Effect of tissue-specific acetylcholinesterase inhibitor C-547 on alpha 3 beta 4 and alpha beta epsilon delta acetylcholine receptors in COS cells

0390752 - FGÚ 2013 RIV NL eng J - Článek v odborném periodiku
Lindovský, Jiří - Petrov, K. - Krůšek, Jan - Reznik, V.S. - Nikolsky, E. E. - Vyskočil, František
Effect of tissue-specific acetylcholinesterase inhibitor C-547 on alpha 3 beta 4 and alpha beta epsilon delta acetylcholine receptors in COS cells.
European Journal of Pharmacology. Roč. 688, 1-3 (2012), s. 22-26. ISSN 0014-2999. E-ISSN 1879-0712
Grant CEP: GA MŠMT(CZ) LC554; GA ČR(CZ) GA202/09/0806; GA AV ČR(CZ) IAA500110905; GA AV ČR(CZ) IAA100110501; GA AV ČR(CZ) IAA5011411
Výzkumný záměr: CEZ:AV0Z50110509
Institucionální podpora: RVO:67985823
Klíčová slova: nicotinic ACh receptor * alpha 3 beta 4 * alpha beta epsilon delta * C-547 * anti-cholinesterase
Kód oboru RIV: ED - Fyziologie
Impakt faktor: 2.592, rok: 2012

The C-547 is the most effective muscle and tissue-specific anticholinesterase among alkylammonium derivatives of 6-methyluracil (ADEMS) acting in nanomolar concentrations on locomotor muscles but not on respiratory muscles, smooth muscles and heart and brain acetylcholine esterases (AChE). When applied systematically it could influence peripheral acetylcholine receptors. The aim of the present study was to investigate the effect of C-547 on rat alpha 3 beta 4 (ganglionic type) and alpha beta epsilon delta (muscle type) nicotinic receptors expressed in COS cells. Currents evoked by rapid application of acetylcholine or nicotine were recorded in whole-cell mode by electrophysiological patch-clamp technique 2-4 days after cell transfection by plasmids coding the alpha 3 beta 4 or alpha beta epsilon delta combination of receptor subunits. In cells sensitive to acetylcholine, the application of C-547 evoked no responses. When acetylcholine was applied during an already running application of C-547, acetylcholine responses were only inhibited at concentrations higher than 10(-7) M. This inhibition is not voltage-dependent, but is accompanied by an increased rate of desensitization. Thus in both types of receptors, effective doses are approximately 100 times higher than those inhibiting AChE in leg muscles and similar to those inhibiting respiratory diaphragm muscles and external intercostal muscles. These observations show that C-547 can be considered for symptomatic treatment of myasthenia gravis and other congenital myasthenic syndromes as an inhibitor of AChE in leg muscles at concentrations much lower than those inhibiting muscle and ganglion types of acetylcholine receptors
Trvalý link: http://hdl.handle.net/11104/0219680