title: PI 3-kinase and PKCζ mediate insulin-induced potentiation of NMDA receptor currents in Xenopus oocytes.
abstract: Insulin modulates N-methyl-d-aspartate (NMDA) receptors in the CNS and potentiates recombinant NMDA receptor currents in Xenopus oocytes. We have previously found that insulin's potentiation of NMDA receptor currents in oocytes occurs in a subunit specific manner and via phosphorylation of specific C-terminal sites by protein tyrosine kinases (PTKs) and C-type protein kinases (PKCs). Insulin-mediated current potentiation of receptors containing the NR2A subunit occurs solely through the activation of PKCs. Activation of phosphoinositide 3-kinase (PI 3-kinase) is known to trigger many insulin-stimulated signaling pathways, and we show here that it lies at a critical step in the insulin-mediated potentiation of NMDA receptor currents. Incubation with the PI 3-kinase inhibitor wortmannin eliminates insulin potentiation of NMDA receptor currents in the oocytes. Atypical isoforms of PKC are known to be activated downstream in the insulin signaling pathway via activation of PI 3-kinase. We demonstrate that the atypical isoform PKC zeta (PKCζ) has a role in insulin-stimulated current potentiation of NR2A-containing NMDA receptors using an isoform-specific pseudosubstrate inhibitor of PKCζ.
authors.affiliation: University of Illinois at Chicago, Department of Biological Sciences and Laboratory for Integrative Neuroscience, Chicago, IL 60607, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Jones
authors.forename: Guey-Ying
authors.initials: GY
authors.lastname: Liao
authors.forename: Robert
authors.initials: R
authors.lastname: Malecki
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Nastasia M
authors.initials: NM
authors.lastname: Salazar
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007328:Insulin / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin; D014982:Xenopus laevis; D000099221:Protein Kinase C zeta
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D016194:Receptors, N-Methyl-D-Aspartate; D000077191:Wortmannin; D000099221:Protein Kinase C zeta; C120997:NR2A NMDA receptor