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.

Modulation of Proton-Gated Channels by Antidepressants

“…However, small molecules of ATDs have numerous targets in the central nervous system (CNS). A classic example is fluoxetine, which affects different potassium channels, − calcium channels, sodium channels, GABAa receptors, nicotinic cholinoreceptor, NMDA, and AMPA types of ionotropic glutamate receptors. Other ATDs also demonstrate complex pharmacological profiles.…”

Acute fluoxetine exposure alters crab anxiety-like behaviour, but not aggressiveness

“…Fluoxetine, a selective serotonin reuptake inhibitor commonly known as Prozac®, causes a transient increase in serotonin levels at synapses throughout the nervous system. Additionally, fluoxetine has been reported to act as an anticonvulsant via the inhibition of persistent sodium channels 8 , an inhibitor of AMPA receptors 9 , and can also increase neurogenesis 10 . Fluoxetine is a popular pharmaceutical drug prescribed for the treatment of a variety of psychological disorders including depression, anxiety, obsessive-compulsive disorders, and nicotine addiction.…”

Inhibition of NMDA receptors through a membrane-to-channel path

“…If MCI requires that uncharged channel blockers enter the membrane, TMM should not exhibit MCI. Similar use of a quaternary ammonium derivative was made to study fluoxetine inhibition of AMPARs 57 . DMM, in contrast, is a tertiary amine and exists in both charged and uncharged forms as a consequence of a pH-dependent equilibrium.…”

“…Pore access from the membrane through fenestrations also occurs in voltage-gated K + channels 66 , 67 and voltage-gated Ca 2+ channels 68 – 70 . Several iGluR ligands were previously proposed to act at hydrophobic sites with unknown properties, including: the NMDAR channel blockers MK-801 29 and ketamine 30 ; the NMDAR inhibitor and local anesthetic bupivacaine; 32 cholesterol, which is required for NMDAR function; 31 the AMPAR inhibitor fluoxetine 57 . In addition, ligands for many other membrane proteins have been proposed to depend on partition into the plasma membrane, including antidepressants 71 , cannabinoids 72 , sphingosine 1-phosphate receptor ligands 73 , and β2-adrenertic receptor agonists 74 .…”