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Artículo

Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors

Dionisio, Leonardo RaulIcon ; Bergé, IgnacioIcon ; Bravo, Matías; Esandi, María del Carmen; Bouzat, Cecilia BeatrizIcon
Fecha de publicación: 03/2015
Editorial: American Society For Pharmacology And Experimental Therapeutics
Revista: Molecular Pharmacology
ISSN: 0026-895X
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15- fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (EG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of a7 or the chimeric a7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of nonneuronal receptors by serum GABA.
Palabras clave: Nicotinic Receptor , Gaba , Acetylcholine , Patch Clamp
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Atribución-NoComercial-SinDerivadas 2.5 Argentina (CC BY-NC-ND 2.5 AR)
Identificadores
URI: http://hdl.handle.net/11336/4378
URL: http://molpharm.aspetjournals.org/content/suppl/2014/12/09/mol.114.095539.DC1.ht
URL: http://molpharm.aspetjournals.org/content/87/3/391.full.pdf
DOI: http://dx.doi.org/10.1124/mol.114.095539
Colecciones
Articulos(INIBIBB)
Articulos de INST.DE INVEST.BIOQUIMICAS BAHIA BLANCA (I)
Citación
Dionisio, Leonardo Raul; Bergé, Ignacio; Bravo, Matías; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors; American Society For Pharmacology And Experimental Therapeutics; Molecular Pharmacology; 87; 3-2015; 391-400
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