title: STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit.
abstract: N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation.
authors.affiliation: Molecular Medicine, Robarts Research Institute, Schulich School of Medicine, the University of Western Ontario, London, Ontario, N6A 5B7, Canada.
authors.forename: Meng
authors.initials: M
authors.lastname: Tian
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Rd, New Haven, CT, 06520, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Molecular Medicine, Robarts Research Institute, Schulich School of Medicine, the University of Western Ontario, London, Ontario, N6A 5B7, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Lei
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Rd, New Haven, CT, 06520, USA.|Departments of Psychiatry, and Neuroscience, Yale University School of Medicine, 230 South Frontage Rd, New Haven, CT, 06520, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T6, Canada.|Neuroscience Research Program, Kleysen Institute for Advanced Medicine, University of Manitoba, Winnipeg, Manitoba, R3E 3J7, Canada.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.affiliation: Molecular Medicine, Robarts Research Institute, Schulich School of Medicine, the University of Western Ontario, London, Ontario, N6A 5B7, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine, the University of Western Ontario, London, Ontario, N6A 5C1, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D009473:Neuronal Plasticity; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D043643:Receptor, Muscarinic M1; D043562:Receptors, G-Protein-Coupled; D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases; C489931:Ptpn5 protein, rat