Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants.
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 muM). 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-(3)H (N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]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.
Gumilar
Fernanda
F
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur, CONICET, Camino La Carrindanga Km 7, B8000FWB Bahía Blanca, Argentina.
Arias
Hugo R
HR
Spitzmaul
Guillermo
G
Bouzat
Cecilia
C
D000109:Acetylcholine / Q000378:metabolism; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004316:Doxepin / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D014101:Torpedo
D000929:Antidepressive Agents, Tricyclic; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D004316:Doxepin; D000639:Amitriptyline; C012058:tenocyclidine; D010622:Phencyclidine; D000109:Acetylcholine; D007099:Imipramine