Non-classical mechanism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine

作者：Barygin Oleg I^*; Komarova Margarita S; Tikhonova Tatiana B; Tikhonov Denis B

来源：European Journal of Neuroscience, 2015, 41(7): 867-875.

DOI：10.1111/ejn.12817

• antidepressants
• glutamate receptors
• molecular modeling
• patch clamp
• pharmacological modulation
• rat

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.

• 出版日期2015-4