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European Bioinformatics Institute European Bioinformatics Institute British outstation of the European Molecular Biology Laboratory Databases Sequences, structures Transcriptomics, Proteomics pathways, models Controlled

  1. European Bioinformatics Institute European Bioinformatics Institute British outstation of the European Molecular Biology Laboratory Databases • Sequences, structures – Transcriptomics, Proteomics – pathways, models Controlled vocabularies – and dictionaries Research groups • Structural Genomics (Thornton) – Molecular Evolution (Goldman) – Text-Mining (Rebholz-Schumman) – Computational Systems Biology (Le Novère) – Statistical array analysis (Huber) – Genomic analysis of regulatory systems (Luscombe) – Functional genomics (Bertone) – > 2 500 000 hits per day

  2. Integration of Dopamine and Glutamate signals by DARPP-32

  3. The brain according to Le Novère The brain according to Le Novère Thalamus sensory input

  4. The brain according to Le Novère The brain according to Le Novère Cortex Thalamus sensory input

  5. The brain according to Le Novère The brain according to Le Novère cortico-striato-thalamic loop Cortex Striatum Thalamus sensory input

  6. The brain according to Le Novère The brain according to Le Novère motor output Cortex Striatum Thalamus sensory input

  7. The brain according to Le Novère The brain according to Le Novère Limbic motivational aspects afferences motor output feelings Cortex Striatum Thalamus sensory input

  8. The brain according to Le Novère The brain according to Le Novère Limbic motivational aspects afferences motor output feelings Cortex Striatum DA Thalamus sensory input

  9. The brain according to Le Novère The brain according to Le Novère Limbic motivational aspects afferences motor output feelings Cortex Striatum DA Thalamus ACh PPTg global activity coordination sensory input

  10. Reminder of the anatomy Reminder of the anatomy thalamus

  11. Dopamine mesotelencephalic pathway Dopamine mesotelencephalic pathway Neocortex Glu Voluntary motion GABA Emotional control Reward DA Learning Parkinson's Striatum Huntington Drug addiction “-” “+” Schizophrenia GPe Thalamus Subthalamic nucleus SNc GPi/SNr

  12. Link between reward and locomotor systems Link between reward and locomotor systems

  13. Multiple afferent signals Multiple afferent signals Fundamental Neuroscience Squire et al. 2 nd ed(2003)

  14. the Medium Spiny Neuron of the striatum the Medium Spiny Neuron of the striatum

  15. A spiny dendrite A spiny dendrite

  16. Biological model of DARPP-32 regulation of DARPP-32 regulation Biological model Cocaine Cocaine haloperidol Amphetamine Amphetamine Antipsychotics Nicotine Nicotine fluoxetine fluoxetine Opiate Opiate Dopamine Dopamine Glutamate Caffein Glutamate Serotonin Serotonin δ µ D2 NMDA NMDA AMPA D1 A2A AMPA 5HT 4/6 5HT4/6 cAMP 2+ Ca cAMP Ca 2+ PP-2B PKA PP-2B PKA DARPP-32 DARPP-32 Thr 34 Thr 34 PP-1 PP-1 striato-pallidal neuron striato-nigral neuron

  17. Biological model of DARPP-32 regulation of DARPP-32 regulation Biological model Cocaine Cocaine haloperidol Amphetamine Amphetamine Antipsychotics Nicotine Nicotine fluoxetine fluoxetine Opiate Opiate Dopamine Dopamine Glutamate Caffein Glutamate Serotonin Serotonin δ µ D2 NMDA NMDA AMPA D1 A2A AMPA 5HT 4/6 5HT4/6 cAMP 2+ Ca cAMP Ca 2+ PP-2B PKA PP-2B PKA Thr 75 Thr 75 PP-2A CDK5 PP-2A CDK 5 DARPP-32 DARPP-32 Thr 34 Thr 34 PP-1 PP-1 striato-pallidal neuron striato-nigral neuron

  18. Biological model of DARPP-32 regulation of DARPP-32 regulation Biological model Cocaine Cocaine haloperidol Amphetamine Amphetamine Antipsychotics Nicotine Nicotine fluoxetine fluoxetine Opiate Opiate Dopamine Dopamine Glutamate Caffein Glutamate Serotonin Serotonin δ µ D2 NMDA NMDA AMPA D1 A2A AMPA 5HT 4/6 5HT4/6 cAMP 2+ Ca cAMP Ca 2+ PP-2B PKA PP-2B CK1 PKA Thr 75 CK1 Thr 75 PP-2A CDK5 PP-2A CDK 5 Ser 137 Ser 137 DARPP-32 DARPP-32 PP-2C PP-2C Thr 34 Thr 34 PP-1 PP-1 striato-pallidal neuron striato-nigral neuron

  19. Biological model of DARPP-32 regulation of DARPP-32 regulation Biological model Cocaine Cocaine haloperidol Amphetamine Amphetamine Antipsychotics Nicotine Nicotine fluoxetine fluoxetine Opiate Opiate Dopamine Dopamine Glutamate Caffein Glutamate Serotonin Serotonin δ µ D2 NMDA NMDA AMPA D1 A2A AMPA 5HT 4/6 5HT4/6 cAMP 2+ Ca cAMP Ca 2+ PP-2B PKA PP-2B CK1 PKA Thr 75 CK1 Thr 75 PP-2A CDK5 PP-2A CDK 5 Ser 137 Ser 137 Ser 102 DARPP-32 Ser 102 DARPP-32 PP-2C CK2 PP-2C CK2 Thr 34 Thr 34 PP-1 PP-1 striato-pallidal neuron striato-nigral neuron

  20. Biological model of DARPP-32 regulation of DARPP-32 regulation Biological model Cocaine Cocaine haloperidol Amphetamine Amphetamine Antipsychotics Nicotine Nicotine fluoxetine fluoxetine Opiate Opiate Dopamine Dopamine Glutamate Caffein Glutamate Serotonin Serotonin δ µ D2 NMDA NMDA AMPA D1 A2A AMPA 5HT 4/6 5HT4/6 cAMP 2+ Ca cAMP Ca 2+ PP-2B PKA PP-2B CK1 PKA Thr 75 CK1 Thr 75 PP-2A CDK5 PP-2A CDK 5 Ser 137 Ser 137 Ser 102 DARPP-32 Ser 102 DARPP-32 PP-2C CK2 PP-2C CK2 Thr 34 Thr 34 PP-1 PP-1 striato-pallidal neuron striato-nigral neuron

  21. Biological model of DARPP-32 regulation of DARPP-32 regulation Biological model Cocaine Cocaine haloperidol Amphetamine Amphetamine Antipsychotics Nicotine Nicotine fluoxetine fluoxetine Opiate Opiate Dopamine Dopamine Glutamate Caffein Glutamate Serotonin Serotonin δ µ D2 NMDA NMDA AMPA D1 A2A AMPA 5HT 4/6 5HT4/6 cAMP 2+ PDE Ca PDE cAMP Ca 2+ PP-2B PKA PP-2B CK1 PKA Thr 75 CK1 Thr 75 PP-2A CDK5 PP-2A CDK 5 Ser 137 Ser 137 Ser 102 DARPP-32 Ser 102 DARPP-32 PP-2C CK2 PP-2C CK2 Thr 34 Thr 34 PP-1 PP-1 striato-pallidal neuron striato-nigral neuron

  22. Negative loops: “russian dolls” Negative loops: “russian dolls” GluR Ca 2 + CaMKII CK1 PP-2B Ser 137 DARPP-32 PP-2C Thr 34 PP-1

  23. All the cybernetics in one system All the cybernetics in one system GluR cAMP Ca 2 + PDE ? CaMKII Thr 75 PKA CK1 PP-2B + + PP-2A CDK5 Ser 137 DARPP-32 PP-2C positive feedback Thr 34 PP-1

  24. All the cybernetics in one system All the cybernetics in one system GluR cAMP Ca 2 + PDE ? CaMKII Thr 75 PKA CK1 PP-2B + + PP-2A CDK5 Ser 137 DARPP-32 PP-2C positive feedback Thr 34 PP-1

  25. All the cybernetics in one system All the cybernetics in one system GluR cAMP Ca 2 + PDE ? CaMKII Thr 75 PKA CK1 PP-2B + - PP-2A CDK5 Ser 137 DARPP-32 PP-2C negative feedback Thr 34 PP-1

  26. All the cybernetics in one system All the cybernetics in one system GluR cAMP Ca 2 + PDE ? CaMKII Thr 75 PKA CK1 PP-2B + - PP-2A CDK5 Ser 137 DARPP-32 PP-2C negative feedback Thr 34 PP-1

  27. All the cybernetics in one system All the cybernetics in one system GluR cAMP Ca 2 + PDE ? CaMKII Thr 75 PKA CK1 PP-2B + - PP-2A CDK5 Ser 137 DARPP-32 PP-2C incoherent feedforward Thr 34 PP-1

  28. Chemical model of DARPP-32 regulation of DARPP-32 regulation Chemical model PKA 2 R 2 cAMP AMP PKA 2 R PDEP PDE PP2Bi PP2BiCa 2 D34:137 PP2B D34:75:137 PKA Ø Ø Ca 2+ D137 D75-137 PP-2C D34 CK1P CK1 D34:75 CDK5 D D75 PP2A PP2AP

  29. Chemical model of DARPP-32 regulation of DARPP-32 regulation Chemical model PKA 2 R 2 cAMP AMP stolen from DOQCS PKA 2 R PDEP PDE PP2Bi PP2BiCa 2 D34:137 PP2B D34:75:137 PKA Ø Ø Ca 2+ D137 D75-137 PP-2C D34 CK1P CK1 D34:75 CDK5 D D75 PP2A PP2AP

  30. Choose the right formalism Choose the right formalism kds kap kcat d[P] E+S ES EP E+P = kdp[EP] - kap[E][P] kcat' kas kdp dt kds kap kcat E+S ES EP E+P catalysis irreversible kas kdp ksa kcat product is consumed E+S ES E+P before rebinding ksd E d[P] [E] kcat = steady-state S P dt Km 1 + [S]

  31. Effect of the wrong choice Effect of the wrong choice 75% 30% 45% PP-2B PP-2B D D D34 D34 PKA PKA elementary PP-2A PP-2A PP-2A PP-2A CDK5 CDK5 steps CDK5 CDK5 PP-2B PP-2B D-75 D-75 D34-75 D34-75 PKA PKA 25% 10% 15% 75% 30% 45% PP-2B PP-2B D34 D D34 D PKA PKA “Michaelis PP-2A PP-2A PP-2A PP-2A CDK5 CDK5 CDK5 CDK5 Menten” PP-2B PP-2B D-75 D-75 D34-75 D34-75 PKA PKA 25% 8% 14% 1) unbalance ; 2) Σ ≠ 100%!!!

  32. Briggs-Haldane Briggs-Haldane [ E ]=[ E 0 ]-[ ES ]

  33. Briggs-Haldane Briggs-Haldane [ E ]=[ E 0 ]-[ ES ] steady-state!!!

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