Artículos de revistas
Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants
Date
2003-12Registration in:
Gumilar, Fernanda Andrea; Arias, Hugo Rubén; Spitzmaul, Guillermo Federico; Bouzat, Cecilia Beatriz; Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants; Pergamon-Elsevier Science Ltd; Neuropharmacology; 45; 7; 12-2003; 964-976
0028-3908
CONICET Digital
CONICET
Author
Gumilar, Fernanda Andrea
Arias, Hugo Rubén
Spitzmaul, Guillermo Federico
Bouzat, Cecilia Beatriz
Abstract
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.