Signal Transduction: Dopamine Signaling

1. Signal Transduction:Dopamine Signaling

2. Outline • Dopamine and dopamine receptors • cAMP-PKA pathway • PLC pathway • Regulation of ion channel by dopamine • Early signal quench and late signal induction

3. Dopamine • Neurotransmitter in Central Neural System • Neurohormone in periphery • important roles in behavior and cognition, voluntary movement, motivation, sleep, mood, attention, working memory, and learning http://www.3dchem.com/molecules.asp?ID=289

4. Synapse in CNS http://blog.lib.umn.edu/trite001/studyinghumananatomyandphysiology/2008/04/dopamine_excitatory_or_inhibit.html

5. Dopamine signaling related disease • Tourette’s syndrome, schizophrenia, and drug and alcohol abuse, Parkinson’s disease etc. • depending on the site of their neurobiological correlate http://www.willamette.edu/~gorr/classes/cs449/brain.html

6. G-protein Coupled receptors • Ligand binding • changing in receptor conformation • Facilitate release of GDP and binding of GTP http://openwetware.org/wiki/BIO254:Gprotein

7. Recall: classfication • Class A (Rhodopsin family) • Highly conserved amino acids (red circles) • Disulphide bridge connecting E1 & E2 • Palmitoylated cysteine in the C-terminal tail • Tilted or kinked due to presence of P’s in TMD’s • Class B (Secretin & Adhesion families) • Relatively long N- terminus w/ disulphide cysteine bridges • No palmitoylation site • Conserved residues and motifs (different from A) • Class C (Glutamate family) • Long N-terminus and C-tail • Ligand-binding domain (yellow) in N- terminus forms disulphide-linked dimer • 2 cys in E1 & E2 form putative disulphide bridge • C1 is short & highly conserved http://www.gpcr.org/7tm/phylo/phylo.html

8. DopamineReceptors • Class -A : Rhodopsin family • D1-like Family: D1 D5 • D2-like Family: D2, D3, and D4 • Grouped by similarity of signal pathways & structure • Two families can have “cross talk”

9. ReceptorStructure • D3 receptor (homo sapiens) 400 aa ECL2 forms ligand binding pocket LCL2 is transient, raising the possibility that interactions between ICL2 and the receptor ionic lock (Ellen Chien, 2010)

10. Outline • Dopamine and dopamine receptors • cAMP-PKA pathway • PLC pathway • Regulation of ion channel by dopamine • Early signal quench and late signal induction

11. D1&D2 signaling overview (KA Neve, 2004)

12. D1&D2 signaling overview (KA Neve, 2004)

13. Recall: Families of G Adapted from Beckerman, Molecular & Cellular Signaling

14. cAMP-PKA pathway D2-like receptor D1-likereceptor Gαs Adenylyl Cyclase 5 Gαi/0 cAMP CREB PKA PP2A (proteinphosphatase) De-P on Thr 75 DARPP-32(PP1 R1B) P on Thr 34 Channel/ transporter PP1 AlbertsMBoC, Fig 15-36, 5th ed.

15. Proteinphosphatase Protein Phosphatase 2A Protein Phosphatase 1 Catalytic subunit scaffolding subunit regulatory subunit (Y Xu, 2006) (A hirschi,2010)

17. cAMP-PKA pathway is in crosstalk and regulated Epac ? MAPK Kinase MAPK MAP Kinase (JM beaulieu,2011)

18. (JM beaulieu,2011)

19. Outline • Dopamine and dopamine receptors • cAMP-PKA pathway • PLC pathway • Regulation of ion channel by dopamine • Early signal quench and late signal

20. D1-likereceptor activate Gq Adapted from Beckerman, Molecular & Cellular Signaling

21. D1 family-PLC pathway ? PKC (JM beaulieu,2011) Alberts, MBoC, Fig 15-39, 5th ed.

22. adenylyl cyclase ion channels phospholipases kinases guanine nucleotide exchange factor kinases  binding protein D2-likereceptoractivateviaGβγ NATURE REVIEWS | DRUG DISCOVERY 604| JULY 2004 | VOLUME 3

23. D2 family-PLC pathway (JM beaulieu,2011)

24. Outline • Dopamine and dopamine receptors • cAMP-PKA pathway • PLC pathway • Regulation of ion channel by dopamine • Early signal quench and late signal induction

25. RECALL Four Families of Ion Channels Voltage-gated Ligand-gated

26. Overview of ion channel regulated (KA Neve, 2004)

27. Dopamineregulated K+ channels • G protein-regulated inwardly rectifying K+ channels (GIRK) D1 receptor GIRK D2 receptor GIRK • voltage-gated K+channels (VGKC) Iks/IA/ID D1 receptor VGKC D2 receptor VGKC PKA PKA PKA PKA Gbγ

28. Dopamineregulated Ca2+ channels • Voltage gated calcium Channel D1 receptor L-type channel N,P/Q type channel D2 receptor L,N,P/Q type of channel PKA/PKC PKA Gbγ

29. Dopamineregulated Na+ channels • Voltage gated Na+ Channel (INat and INap) • D1 receptor PKA pathwayα-subunit Ser573 phosphorylation transient Na+ • current D1 receptor persistentNa+current • D2 receptor Na+ channels PKA/PKC PKA inhibition Gbγ

30. Dopamine regulated glutamate receptors • D1 receptor • D2 receptor NMDA AMPA GABA PKA Gbγ PKA inhibition/ NMDA AMPA GABA ? Gbγ

31. Direct interaction between DA receptor and ion channels -- D1 receptor N-type Calcium Channels -- D1 receptor NMDA PKA D2 receptor NMDA D5 receptor GABA

32. Outline • Dopamine and dopamine receptors • cAMP-PKA pathway • PLC pathway • Regulation of ion channel by dopamine • Early signal quench and late signal induction

33. DA receptor early signal shutdown & late signal induction (JM beaulieu,2011)

34. RGS deactivate Gα RGS 9-2 regulates D2-like receptor signaling Probably cooperate with RGS 7, mediated by R7BP

35. GRK GRKdeactivateGPCR • GPCR Kinase • 3 families: • GRK1 like (1 and 7) retina specific 1  rhodopsin 7 iodopsin • GRK2-like (2 and 3) • GRK4-like (4,5 and 6)

36. Arrestin and downstream pathway • arrestin 1 (rod) arrestin 4 (cone) β-arrestin 1 2 (widely) β-arrestin 2 (widely) • Binds phosphorylated GRK 1.Recruit Clathrininternalizationrecycle or degrade GPCR 2.Scaffold PP2A and Akt(PKB)  dephosphorylate (deactivate)Akt http://www.fz-juelich.de/isb/isb-2/topics/arrestin

37. Akt activation pathway mTOR http://www.nature.com/onc/journal/v24/n50/fig_tab/1209099f1.html

38. Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase NMDA AMPA (JM beaulieu,2011)

39. Summary • D1 and D2 families of dopamine receptor have distinct effect on cAMP-PKA pathway, but also share similar effect in PLC pathway • D1 and D2 families have different effect on regulation of ion channels • Dopamine receptor signal can be shut down and induce late signal(Akt pathway)

40. Reference • Beaulieu, J. M. and R. R. Gainetdinov (2011). "The Physiology, Signaling, and Pharmacology of Dopamine Receptors." Pharmacological Reviews 63(1): 182. • Cave, J. W. and H. Baker (2009). "Dopamine systems in the forebrain." Development and Engineering of Dopamine Neurons: 15-35. • Chien, E. Y. T., W. Liu, et al. (2010). "Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist." Science 330(6007): 1091. • Hirschi, A., M. Cecchini, et al. (2010). "An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein." Nature structural & molecular biology • Kienast, T. and A. Heinz (2006). "Dopamine and the diseased brain." Current Drug Targets-CNS &# 38; Neurological Disorders 5(1): 109-131. • Kurachi, Y. and M. Ishii (2004). "Cell signal control of the G protein-gated potassium channel and its subcellular localization." The Journal of Physiology 554(2): 285. • Lüscher, C. and P. A. Slesinger (2010). "Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease." Nature Reviews Neuroscience 11(5): 301-315. • Missale, C., C. Fiorentini, et al. (2010). "The neurobiology of dopamine receptors: evolution from the dual concept to heterodimer complexes." Journal of Receptors and Signal Transduction 30(5): 347-354. • Neve, K. A., J. K. Seamans, et al. (2004). "Dopamine receptor signaling." Journal of Receptors and Signal Transduction 24(3): 165-205. • Xu, Y., Y. Xing, et al. (2006). "Structure of the protein phosphatase 2A holoenzyme." Cell 127(6): 1239-1251.