title: Mechanisms of NOS1AP action on NMDA receptor-nNOS signaling.
abstract: NMDA receptors (NMDAR) are glutamate-gated calcium channels that play pivotal roles in fundamental aspects of neuronal function. Dysregulated receptor function contributes to many disorders. Recruitment by NMDARs of calcium-dependent enzyme nNOS via PSD95 is seen as a key contributor to neuronal dysfunction. nNOS adaptor protein (NOS1AP), originally described as a competitor of PSD95:nNOS interaction, is regarded an inhibitor of NMDAR-driven nNOS function. In conditions of NMDAR hyperactivity such as excitotoxicity, one expects NOS1AP to be neuroprotective. Conditions of NMDAR hypoactivity, as thought to occur in schizophrenia, might be exacerbated by NOS1AP. Indeed GWAS have implicated NOS1AP and nNOS in schizophrenia. Several studies now indicate NOS1AP can mediate rather than inhibit NMDAR/nNOS-dependent responses, including excitotoxic signaling. Yet the concept of NOS1AP as an inhibitor of nNOS predominates in studies of human disease genetics. Here we review the experimental evidence to evaluate this apparent controversy, consider whether the known functions of NOS1AP might defend neurons against NMDAR dysregulation and highlight specific areas for future investigation to shed light on the functions of this adaptor protein.
authors.affiliation: Molecular Signalling Laboratory, Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland Kuopio, Finland ; Turku Centre for Biotechnology, Abo Akademi University and University of Turku Turku, Finland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Courtney
authors.affiliation: Molecular Signalling Laboratory, Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland Kuopio, Finland.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Li
authors.affiliation: Jack Gill Center for Biomolecular Science, Department Psychological and Brain Sciences, Indiana University Bloomington, IN, USA.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Lai
keywords: NMDA receptor; NOS1AP; PDZ; PSD95; excitotoxicity; nNOS; nitric oxide; schizophrenia