Abstract
The targets for tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) are known to be the serotonin and norepinephrine transport (reuptake) proteins which are embedded in presynaptic nerve terminals and function to bring these neurotransmitters from the synaptic cleft back into the presynaptic neuron. Using a combination of intrinsic and extrinsic fluorescence quenching, Stern-Volmer analysis, and protease protection assays, we have shown that therapeutics from each of these three classes of antidepressants bind to the extracellular S1S2 domain of the NR1-1b subunit of the NMDA receptor. These results are in agreement with recent work from our lab demonstrating the interaction of antidepressants with the S1S2 domain of the GluR2 subunit of the AMPA receptor, another member of the ionotropic glutamate receptor subfamily, as well as work from other labs, and continue the discussion of the involvement of ionotropic glutamate receptors in depression.
Highlights
Ionotropic glutamate receptors are a family of ligand-gated ion channels located on the postsynaptic neural membrane which open in response to extracellular binding of the neurotransmitter glutamate
Intrinsic Tryptophan Fluorescence Demonstrates Binding of 5 tricyclic antidepressants (TCAs) and 3 selective serotonin reuptake inhibitors (SSRIs) to the NMDA NR1-1b S1S2 Domain
By comparing the emission spectrum of the apo NMDA NR11b S1S2 domain to antidepressant bound complexes, it is possible to determine if the antidepressant has bound to the S1S2 domain and caused a change in the environment
Summary
Ionotropic glutamate receptors (iGluRs) are a family of ligand-gated ion channels located on the postsynaptic neural membrane which open in response to extracellular binding of the neurotransmitter glutamate These receptors play an important role in memory, learning, development, and neural plasticity. The intrinsic and extrinsic fluorescence studies presented here add to the body of knowledge suggesting a role for NMDA receptors in antidepressant activities They demonstrate that five tricyclic antidepressants (TCAs) (desipramine, trimipramine, maprotiline, nortriptyline, and imipramine), four selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, paroxetine, sertraline, and fluoxetine), and one selective norepinephrine reuptake inhibitor (SNRI) (venlafaxine), see Figure 2, bind to the S1S2 domain of the NR1-1b subunit of the NMDA receptor. The only antidepressant that showed no binding in any of our studies, at concentrations as high as 5.21 mM, was the SSRI citalopram
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