Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants

Authors
Gumilar, Fernanda Andrea; Arias, Hugo Rubén; Spitzmaul, Guillermo Federico; Bouzat, Cecilia Beatriz
Publication Year
2003
Language
English
Format
article
Status
Published version
Description
In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR. Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 μM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl) cyclohexyl)-3,4-piperidine ([3H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.
Fil: Gumilar, Fernanda Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Arias, Hugo Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Western University of Health Sciences, California; Estados Unidos
Fil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Subject
ACETYLCHOLINE
NICOTINIC RECEPTOR
NONCOMPETITIVE INHIBITOR
TRICYCLIC ANTIDEPRESSANT
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/53354