Artículo
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors
Fecha de publicación:
12/2006
Editorial:
American Society for Pharmacology and Experimental Therapeutics
Revista:
Molecular Pharmacology
ISSN:
0026-895X
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Nicotinic receptors (AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of alpha7 AChRs using the high conductance form of the alpha7-5HT3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. Interestingly, pyrantel is a more potent agonist of alpha7 than ACh. To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle epsilon subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of alpha7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel.
Palabras clave:
Cys Loop Receptor
,
Nicotinic Receptor
,
Patch Clamp
,
Anthelmintic
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Colecciones
Articulos(IFEC)
Articulos de INST. DE FARMACOLOGIA EXPERIMENTAL DE CORDOBA
Articulos de INST. DE FARMACOLOGIA EXPERIMENTAL DE CORDOBA
Articulos(INIBIBB)
Articulos de INST.DE INVEST.BIOQUIMICAS BAHIA BLANCA (I)
Articulos de INST.DE INVEST.BIOQUIMICAS BAHIA BLANCA (I)
Articulos(SEDE CENTRAL)
Articulos de SEDE CENTRAL
Articulos de SEDE CENTRAL
Citación
Bartos, Mariana; Rayes, Diego Hernán; Bouzat, Cecilia Beatriz; Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 70; 4; 12-2006; 1307-1318
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