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Signal Transduction: Dopamine Signaling

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Signal Transduction:Dopamine Signaling

Outline

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

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

Synapse in CNS

http://blog.lib.umn.edu/trite001/studyinghumananatomyandphysiology/2008/04/dopamine_excitatory_or_inhibit.html

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

G-protein Coupled receptors

• Ligand binding • changing in

receptor conformation

• Facilitate release of GDP and binding of GTP

http://openwetware.org/wiki/BIO254:Gprotein

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

Recall: classfication

Dopamine Receptors• 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”

Receptor Structure• D3 receptor (homo sapiens)

(Ellen Chien, 2010)

400 aa

ECL2 forms ligand binding pocket

LCL2 is transient, raising the possibilitythat interactions between ICL2 and the receptorionic lock

Outline

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

D1&D2 signaling overview

(KA Neve, 2004)

D1&D2 signaling overview

(KA Neve, 2004)

Recall: Families of GFamily Gene

VarientsEffectors 2nd

MessengerAssociation

Gs s(S), s(L) adenylyl cyclase cAMP

olf adenylyl cyclase cAMP Olfactory

Gi i1,i2,i3, adenylyl cyclase cAMP

0a, 0b phospholipaseC IP3, DAG Brain

t1, t2cGMP-PDE cGMP Retina

gust phospholipaseC IP3, DAG Gustatory

z adenylyl cyclase cAMP

Gq q,11,14,

15, 16

phospholipaseC IP3, DAG

G12 12, 13 Rho-GEF Rho

Adapted from Beckerman, Molecular & Cellular Signaling

Alberts MBoC, Fig 15-36, 5th ed.

Gαs

Adenylyl Cyclase 5

cAMP

PKA

DARPP-32(PP1 R1B)

PP2A (protein phosphatase)

D1-like receptor

PP1

cAMP-PKA pathway

CREB

P on Thr 34

D2-like receptor

Gαi/0

De-P on Thr 75

Channel/transporter

Protein phosphatase

(Y Xu, 2006)

Protein Phosphatase 2A

Catalytic subunit

regulatory subunitscaffolding subunit

Protein Phosphatase 1

(A hirschi,2010)

cAMP-PKA pathway is in crosstalk and regulated

MAPK

Epac

?MAP Kinase

MAPK Kinase

(JM beaulieu,2011)

(JM beaulieu,2011)

Outline

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

D1-like receptor activate GqFamily Gene

VarientsEffectors 2nd

MessengerAssociation

Gs s(S), s(L) adenylyl cyclase cAMP

olf adenylyl cyclase cAMP Olfactory

Gi i1,i2,i3, adenylyl cyclase cAMP

0a, 0b phospholipaseC IP3, DAG Brain

t1, t2cGMP-PDE cGMP Retina

gust phospholipaseC IP3, DAG Gustatory

z adenylyl cyclase cAMP

Gq q,11,14,

15, 16

phospholipaseC IP3, DAG

G12 12, 13 Rho-GEF Rho

Adapted from Beckerman, Molecular & Cellular Signaling

D1 family-PLC pathway

PKC

Alberts, MBoC, Fig 15-39, 5th ed.(JM beaulieu,2011)

?

D2-like receptor activate via Gβγ

NATURE REVIEWS | DRUG DISCOVERY 604| JULY 2004 | VOLUME 3

ion channels

adenylyl cyclase

phospholipases

guanine nucleotide exchange factor

kinases

binding protein

kinases

D2 family-PLC pathway

(JM beaulieu,2011)

Outline

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

Four Families of Ion ChannelsIon Channel Selectivity Subunit Topology Channel assembly

6TM cation 6TM, loop24 TM, 4 loops

Tetrameric, Monomeric

Calcium Ca2+

HCN Na+, K+

Potassium K+

Sodium Na+

Voltage-gated ion 10-18IM Dimeric

ClC Cl-

Cys-loop receptor 4TM Pentameric

nAChR Cations

GABAA,C Anions (Cl-)

Glycine Anions (Cl-)

5-HT3 Cations

Glutamate recep’r 3TM, loop Tetrameric

AMPA Na+, K+

Kainate Na+, K+

NMDA Ca2+

Liga

nd-g

ated

Vol

tage

-gat

edRECALL

Overview of ion channel regulated

(KA Neve, 2004)

Dopamine regulated 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

Gbγ

PKA

PKA

PKA

PKA

Dopamine regulated 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

Dopamine regulated Na+ channels

• Voltage gated Na+ Channel (INat and INap)• D1 receptor PKA pathwayα-subunit Ser

573 phosphorylation transient Na+ • current D1 receptor persistent Na+

current • D2 receptor Na+ channels

PKA/PKC

PKA inhibition

Gbγ

Dopamine regulated glutamate receptors

• D1 receptor

• D2 receptor

NMDAAMPAGABA

PKA inhibition/NMDAAMPAGABA

PKA

Gbγ

Gbγ

?

Direct interaction between DA receptor and ion channels

-- D1 receptor N-type Calcium Channels-- D1 receptor NMDA PKA D2 receptor NMDA D5 receptor GABA

Outline

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

DA receptor early signal shutdown & late signal induction

(JM beaulieu,2011)

RGS deactivate Gα

RGS 9-2 regulates D2-like receptor

signaling

Probably cooperate with

RGS 7, mediated by

R7BP

GRK deactivate GPCR

• 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)

GRK

Arrestin and downstream pathway

• arrestin 1 (rod) arrestin 4 (cone) β-arrestin 1 2 (widely) β-arrestin 2 (widely)

• Binds phosphorylated GRK1.Recruit Clathrininternalizationrecycle or degrade GPCR2.Scaffold PP2A and Akt(PKB) dephosphorylate (deactivate)Akt

http://www.fz-juelich.de/isb/isb-2/topics/arrestin

Akt activation pathway

mTOR

http://www.nature.com/onc/journal/v24/n50/fig_tab/1209099f1.html

NMDA

AMPA

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase

(JM beaulieu,2011)

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)

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.