Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 41, Issue 7, Pages 867-875Publisher
WILEY-BLACKWELL
DOI: 10.1111/ejn.12817
Keywords
antidepressants; glutamate receptors; molecular modeling; patch clamp; pharmacological modulation; rat
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Funding
- RFBR [13-04-00724, 12-04-00454]
- Russian Academy of Sciences (Molecular and Cell Biology program)
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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 Ca2+-permeable and Ca2+-impermeable -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca2+-impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC50 value for the inhibition of Ca2+-permeable AMPA receptors in giant striatal interneurons was 43 +/- 7m. The inhibition of Ca2+-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.
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