title: Non-classical mechanism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine.
abstract: Antidepressants have many targets in the central nervous system. A growing body of data demonstrates the influence of antidepressants on glutamatergic neurotransmission. In the present work, we studied the inhibition of native Ca(2+)-permeable and Ca(2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca(2+)-impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC50 value for the inhibition of Ca(2+)-permeable AMPA receptors in giant striatal interneurons was 43 ± 7 μM. The inhibition of Ca(2+)-permeable AMPA receptors was voltage dependent, suggesting deep binding in the pore. However, the use dependence of fluoxetine action differed markedly from that of classical AMPA receptor open-channel blockers. Moreover, fluoxetine did not compete with other channel blockers. In contrast to fluoxetine, its membrane-impermeant quaternary analog demonstrated all of the features of channel inhibition typical for open-channel blockers. It is suggested that fluoxetine reaches the binding site through a hydrophobic access pathway. Such a mechanism of block is described for ligands of sodium and calcium channels, but was never found in AMPA receptors. Molecular modeling suggests binding of fluoxetine in the subunit interface; analogous binding was proposed for local anesthetics in closed sodium channels and for benzothiazepines in calcium channels.
authors.affiliation: I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Torez pr. 44, Saint Petersburg, 194223, Russia.
authors.forename: Oleg I
authors.initials: OI
authors.lastname: Barygin
authors.forename: Margarita S
authors.initials: MS
authors.lastname: Komarova
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Tikhonova
authors.forename: Denis B
authors.initials: DB
authors.lastname: Tikhonov
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001665:Binding Sites; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003198:Computer Simulation; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D003959:Diamines / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D003959:Diamines; C406748:IEM 1925; D000644:Quaternary Ammonium Compounds; D018091:Receptors, AMPA; D005473:Fluoxetine; D002118:Calcium
keywords: antidepressants; glutamate receptors; molecular modeling; patch clamp; pharmacological modulation; rat