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SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA

SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA MICHAEL SALTER MD PHD FRSC U TORONTO CENTRE FOR THE STUDY OF PAIN. Na + Ca 2+. Na + Ca 2+. N. Gly. 4. 4. 3. 3. 1. 1. 2. 2. C. K +. Y P. Y P. K +. Y P. Y P. Y P. Phosphorylation

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SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA

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  1. SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA MICHAEL SALTER MD PHD FRSC U TORONTO CENTRE FOR THE STUDY OF PAIN

  2. Na+ Ca2+ Na+ Ca2+ N Gly 4 4 3 3 1 1 2 2 C K+ YP Y P K+ YP YP Y P Phosphorylation by Src kinase NMDA Receptor Complex N Glu Mg2+ Cytoplasmic Cytoplasmic C Scaffolding/ Signalling Proteins Wang and Salter, Nature369: 233, 1994 Yu et al., Science275: 674, 1997 Lu et al, Science279: 1363, 1998 Huang et al, Neuron29: 485, 2001 Pelkey et al, Neuron 34: 127, 2002 Yu and Salter, Nature396: 469, 1998

  3. NMDA kinase activator phosphatase inhibitor 2 min 0.1 0.01 0.001 phosphatase kinase inhibitor 2 min 0.1 0.01 0.001

  4. Src upregulation of NMDA receptors in pathologic pain states Suppression of Src upregulation of NMDA receptors by neuregulin 1 – ErbB4 signaling

  5. Src upregulation of NMDA receptors in pathologic pain states Suppression of Src upregulation of NMDA receptors by neuregulin 1 – ErbB4 signaling

  6. ND2 NMDA receptor complex Gingrich et al, PNAS101: 6237-6242, 2004

  7. ND2 Tat Src40-49 NMDA receptor complex Src 40-49 Aarts et al., Science298: 846, 2002

  8. Experimental models of chronic injury of a peripheral nerve Experimental model of chronic constriction injury of a sensory nerve Spinal cord 20 Sham 15 50% Threshold (g) 10 L5DRG 5 Nerve injury 0 0 1 2 3 4 Time after surgery (weeks)

  9. PNI-induced behaviours are reversed by Src40-49Tat

  10. PNI-induced behaviours are reversed by Src40-49Tat Approximately 100-1000x more potent than morphine

  11. Src40-49Tat i.v. suppresses Src-ND2 association

  12. PNI-induced increase in GluN2B tyrosine phosphorylation is reversed by Src40-49Tat

  13. PNI-induced behaviours are suppressed Src-/- mice

  14. Effect of Src40-49Tat is occluded in Src null mice

  15. Liu et al. Nature Medicine14:1325-1332, 2008

  16. Src upregulation of NMDA receptors in pathologic pain states Suppression of Src upregulation of NMDA receptors by neuregulin 1 – ErbB4 signaling

  17. 40 58 KPASADGHRGPSAAFVPPA Lu et al, Science279: 1363, 1998

  18. Src Src Src Na+ STEP CAKb Csk CAKb CAKb Basal Induction Potentiated Tetanus / Theta burst Input Glu Glu Glu Mg2+ AMPAR KAIR NMDAR P P ND2 ND2  ND2  - - + PTPα P Ca2+ GPCR, EphB and other signaling AMPAR KAIR Salter & Pitcher, 2011

  19. Trends Cardiovasc Med 2:80-86, 2003 ErbB Family of Receptors

  20. ErbB4 interacts with PSD-95 at excitatory synapses Huang et al, Neuron 26:443-455, 2000

  21. ErbB4 localizes in the PSD in spines Ma et al, J. Neurosci. 23:3164 –3175, 2003

  22. NRG1: 8p12-p21 ERBB4: 2p33.3-q34 Mei & Xiong Nature Rev Neuroci9:437–452, 2008

  23. Huang et al, Neuron 26:443-455, 2000

  24. Pitcher et al, NeuroReport19:139-143, 2008

  25. Loss of function of ErbB4 enhances tbLTP in the hippocampal CA1 Pitcher et al, NeuroReport19:139-143, 2008

  26. NRG1b prevents but does not reverse theta burst stimulation (TBS)-induced LTP in the hippocampal CA1 Pitcher et al, Nature Medicine17:470-478, 2011

  27. NRG1b has no effect on basal NMDAR EPSCs in CA1

  28. NRG1b prevents endogenous Src activation-induced potentiation of NMDAR EPSCs in CA1 Neuregulin PreventsEndogenous Src Activation-Dependent Potentiation of Schaffer Collateral-Evoked NMDA Excitatory Postsynaptic Currents Normalized NMDA EPSC Amplitude (%)

  29. ErbB4 mediates NRG1b suppression of Src potentiation of NMDAR EPSCs in CA1

  30. NRG1b prevents endogenous Src potentiation of NMDAR EPSCs in Prefrontal Cortex

  31. NRG1b–ErbB4 signaling prevents TBS-induced GluN2B phosphorylation in hippocampal CA1

  32. NRG1b does not affect LTP in Src-/- slices

  33. EPQ(pY)EEIPIA enhancement of synaptic transmission is lost in Src-/- slices

  34. NRG1b signaling reduces depolarization of CA1 neurons during the period of TBS

  35. NRG1b signaling reduces depolarization of CA1 neurons during the period of TBS

  36. NRG1b signaling reduces depolarization of CA1 neurons during the period of TBS Control NRG1b

  37. NRG1 X ErbB4 Enhanced Synaptic Plasticity   Ca2+ Theta Burst Stimulation Glu Glu Glu Glu NRG1 Mg2+ + Basal Synaptic Transmission AMPAR KAIR NMDAR ErbB4 ErbB4 - Physiological Synaptic Plasticity ND2 ND2 ND2 ND2 Ca2+ Src Src Src Src NRG1 + AMPAR KAIR ErbB4 - Suppressed Synaptic Plasticity Salter & Pitcher, FEBS Letters, 2011

  38. Graham Pitcher Declan Ali Rand Askalan David Ng Jon Davidow Jeff Gingrich Yueqiao Huang Lorraine Kalia Gary Keil Simon Beggs Ken Pelkey Xuejun Liu Xian-Min Yu Yutian Wang Janice Hicks Sandra Singhroy David Wong U of T Evelyn Lambe Nathalie Goodfellow John MacDonald Mt. Sinai Hospital John Roder You-Ming Lu U. Alabama / Georgia Health Sci. U. Lin Mei Ran-Sook Woo Yang Z. Huang Tufts Univ Kathleen Yee UNC Richard Weinberg

  39. Declan Ali Rand Askalan Simon Beggs Jon Davidow Jeff Gingrich Yueqiao Huang Lorraine Kalia Gary Keil Chun Kwan Ken Pelkey Xuejun Liu Yi Nong Graham Pitcher Tuan Trang Xian-Min Yu Yutian Wang Wenbo Zhang Janice Hicks Sandra Singhroy David Wong Mt. Sinai Hospital John Roder You-Ming Lu Yale University Paul Lombroso Tri-Hung Nguyen U of T / Robarts John MacDonald Wei-Yang Lu Zhigang Xiong U of T Evelyn Lambe Nathalie Goodfellow U. Alabama / Georgia Health Sci. U. Lin Mei Ran-Sook Woo Yang Z. Huang U of T / UBC Yutian Wang William Ju Reza Ahmadian N I H Robert Wenthold Ronald Petralia Tufts Univ Kathleen Yee UNC Richard Weinberg Sapporo Medical Univ. Terukatsu Sasaki Hiroshi Aoto

  40. PNI-induced increase in GluN2B tyrosine phosphorylation is suppressed in Src-/- mice

  41. Liu et al. Nature Medicine14:1325-1332, 2008

  42. Na+ Ca2+ N Gly 4 4 3 3 1 1 2 2 C K+ YP Y P YP YP Y P Phosphorylation by Src kinase NMDA Receptor Complex N Glu Mg2+ Cytoplasmic Cytoplasmic C Scaffolding/ Signalling Proteins

  43. PNI-induced cold sensitization reversed by Src40-49Tat

  44. Genetic Susceptibility (Neuregulin1 (NRG1) & ErbB4) Schizophrenia Human ErbB4 (top) Human ErbB4 (side) NMDAR Hypofunction Hippocampus & Theta Wave (EEG) PCP Ketamine

  45. Effect of NRG-1b on NR2 Tyrosine Phosphorylation at Schaffer Collateral CA1 Synapses pY pY NR2 NR2

  46. Src hypofunction induced by enhanced NRG1-ErbB4 signaling in schizophrenia Hahn, C-G., Nat. Med.17:425-427, 2011

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