title: The PSD-95/nNOS complex: new drugs for depression?
abstract: Drug treatment of major depressive disorder is currently limited to the use of agents which influence monoaminergic neuronal transmission including inhibitors of presynaptic transporters and monoamine oxidase. Typically improvement in depressive symptoms only emerges after several weeks of treatment, suggesting that downstream neuronal adaptations rather than the elevation in synaptic monoamine levels are responsible for antidepressant effects. In recent years, the NMDA receptor has emerged as a promising target for treating CNS disorders including stroke, pain and depression. In this review, we outline the molecular mechanisms underlying NMDA receptor signalling in neurons and in particular provide an overview of the role of the NMDAR/PSD-95/nNOS complex in CNS disorders. We discuss novel drug developments made that suggest the NMDAR/PSD-95/nNOS complex as a potential target for the treatment of depression. The review also provides examples of how PDZ-based protein-protein interactions can be exploited as novel drug targets for disease.
authors: Molecular Neuropharmacology, Department of Physiology, Trinity College, Dublin 2, Ireland.
authors: Marika V
authors: MV
authors: Doucet
authors: Andrew
authors: A
authors: Harkin
authors: Kumlesh K
authors: KK
authors: Dev
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D052248:Nitric Oxide Synthase Type I; D051528:Guanylate Kinases