Ionotropic glutamate receptors (iGluRs), a family of ligand-gated ion channels, are responsible for the majority of fast excitatory neurotransmission in the central nervous system and play an integral role in cognition, learning, and neural plasticity. Misregulation of these receptors is implicated in the ischemic stroke cascade, schizophrenia, and Alzheimer's, Huntington's, and Parkinson's disease. In addition, the main excitatory neurotransmitter of iGluRs, glutamate, has been shown to be involved with depression. Although antidepressants have been prescribed for more than 40 years, the pathophysiology of depression and the action of antidepressants are not completely understood. Studies are now suggesting a possible link between iGluRs, depression, and antidepressant action. While the soluble extracellular S1S2 natural agonist binding domain of the GluR2 subunit of the (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptor is well characterized, the binding sites of regulators of the receptor have yet to be structurally determined. We have previously shown that the binding sites of two endogenous neurosteroids, pregnenolone sulfate (PS) and 3α-hydroxy-5β-pregnan-20-one sulfate (PregaS), reside in the S1S2 domain of the GluR2 subunit. The studies presented here show that PS and PregaS, both of which down-regulate AMPA receptors, have distinct binding sites on the GluR2-S1S2 domain. In addition, this work provides the first evidence that the tricyclic antidepressants (TCAs) trimipramine, imipramine, nortriptyline, and maprotiline bind to the GluR2-S1S2 domain, thereby suggesting a direct interaction between TCAs and iGluRs. Interestingly, the selective serotonin reuptake inhibitor fluoxetine does not bind to the GluR2-S1S2 domain. Using intrinsic fluorescence emission spectroscopy in conjunction with competition binding assays and Stern-Volmer analyses, it is shown that trimipramine, imipramine, nortriptyline, maprotiline, and desipramine have distinct binding sites on the GluR2-S1S2 domain and all five elicit unique conformational changes upon binding. Together these results ultimately suggest the possibility of differential regulation of AMPA receptors by TCAs.
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