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G-protein-coupled receptors
(GPCRs)
mchuang@ntu.edu.tw
Graduate Institute of Anatomy and Cell Biology
&
5
Pharmacol Rev. 2004 Sep;56(3):371-85.
Characteristics of GPCRs
Extracellular
NH2
7 transmembrane domains
3 intracellular loops
Cytoplasmic
3 extracellular loops
HOOC
A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling.
GPR30 is uniquely localized to the endoplasmic reticulum
Revankar CM et al., Science. 2005. 307:1625.
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G-protein-coupled receptors (GPCRs)
8
Class A
Rhodopsin like
Class B
Secretin like
Class C
Class D
Fungal pheromone
Class E
Frizzled/Smoothened family
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NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | AUGUST 2002 | 599-608
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NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | OCTOBER 2002 | 808-820
GRAFS system
Five main classes: Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin
Orphan receptors
(unknown ligands)
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Annu Rev Pharmacol Toxicol. 2013;53:127-46
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http://stke.sciencemag.org/content/vol0/issue2002/images/data/CMP_6634/DC1/science3.jpg, by R. Iyengar's laboratory
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NATURE | VOL 415 | 10 JANUARY 2002 206-212
G protein action
ligand
1.
GPCR
2.
GPCR
(GEF)
GTP
GDP
GDP
3.
4.
effector
GPCR
GDP
Pi
GPCR
stops
(GAP)
GTP
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second messenger
Kobilkas group
Nature. 2011 Jul 19;477(7366):549-55.
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 3 | SEPTEMBER 2002 | 639-650
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GPCR
G protein
effector
activities
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Modified from TRENDS in Pharmacological Sciences Vol.22 No.7 July 2001, 368-376
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31 MAY 2002 VOL 296 SCIENCE, 1636-1639
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NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | MARCH 2002 | 188
Desensitization
Desensitization
(receptor level)
(A) Rapid: phosphorylation (sec~min)
(B) Slow: degradation or expression (hours)
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Desensitization
(A) Rapid: phosphorylation (sec~min)
1. Second-messenger kinase (PKA, PKC):
uncouple GPCR from G protein
ligand independent
heterologous desensitization
Desensitization
GPCR kinase (GRK) phosphorylation
arrestin 1-arrestin 4
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 3 | SEPTEMBER 2002 | 639-650
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SCIENCE VOL 297 26 JULY 2002
Desensitization
(Post-receptor level)
RGS (regulator of G-protein signaling)
a. GTPase-activating proteins
b. accelerate GTP hydrolysis
c. >25 members, for selectivity
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Desensitization by
regulator of G-protein signalling (RGS)
Internalization
Internalization
Functions:
1. Desensitization
2. Resensitization
3. Signal transduction
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Internalization
Types:
Clathrin-coated pits
-arrestin
Caveolae-mediated
Lipid rafts: signalling
Uncoated vesicles
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Function 1: Desensitization
-arrestin-dependent internalization of GPCRs
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NATURE REVIEWS | NEUROSCIENCE VOLUME 2 | OCTOBER 2001 | 727-733
Function 2: Resensitization
P
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Pharmacol Rev 53:124, 2001
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NATURE REVIEWS | NEUROSCIENCE VOLUME 2 | OCTOBER 2001 | 727-733
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TRENDS in Pharmacological Sciences Vol.28 No.8 417
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J Biol Chem. 2015 Jan 20. [Epub ahead of print]
G-protein-independent
signalling
G-protein-independent signalling
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Scaffold Proteins
3
2
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Circ Res. 2002;91:672-680
PDZ: PSD-95/Discs-large/ZO-1
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Circ Res. 2002;91:672-680
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TRENDS in Biochemical Sciences Vol.26 No.5 May 2001, 291-297
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Circ Res. 2002;91:672-680
Ca2+ release
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TRENDS in Biochemical Sciences Vol.26 No.5 May 2001, 291-297
3. GPCR/-arrestin interaction
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Circ Res. 2002;91:672-680
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TRENDS in Biochemical Sciences Vol.26 No.5 May 2001, 291-297
46
NATURE | VOL 415 | 10 JANUARY 2002 206-212
Transactivation
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NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 85
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Trends Endocrinol Metab. 2006 Mar;17(2):48-54
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Trends Endocrinol Metab. 2006 Mar;17(2):48-54
Oligomerization
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NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | OCTOBER 2002 | 808-820
52
NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 3 | SEPTEMBER 2002 | 639-650
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TRENDS in Pharmacological Sciences Vol.26 No.1 January 2005
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EMBO reports VOL 7 | NO 11 | 2006, p. 1096
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NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | OCTOBER 2002 | 808-820
Drug discovery
GPCR Drugs >$20B annual sales
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Obesity
Cardiovascular Disease
Inflammation
Cancer
Diabetes
Alzheimers Disaese
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Drug screening
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 3 | SEPTEMBER 2002 | 639-650
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CART
Constitutively Active Receptor Technology
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Diseases - GPCRs
DISEASE
OVERACTIVE KNOWN GPCRs
---------------------------------------------------------------Schizophrenia
5HT2A, D4
---------------------------------------------------------------Depression
5HT2A
---------------------------------------------------------------Hyperthyroidism
Thyrotropin
---------------------------------------------------------------Hypertension
Angiotensin AT1A
---------------------------------------------------------------Asthma
Adenosine A1
---------------------------------------------------------------Melanoma
MC-1
---------------------------------------------------------------Retinitis Pigmentosa
Rhodopsin
---------------------------------------------------------------63
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Nat Rev Drug Discov. 2011 Jan;10(1):47-60.
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Nat Rev Drug Discov. 2011 Jan;10(1):47-60.
inactive
active
66
CART
Constitutively Active Receptor Technology
Inverse agonists: block ligand-independent activity
Selective molecules: one ligand to multiple receptors
Agonists
Allosteric modulators
(Antagonist: block ligand-dependent activity)
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Summary
68
Internalization
Scaffold proteins
GRK
PKA
PKC
signaling
RGS
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Modified from TRENDS in Pharmacological Sciences Vol.22 No.7 July 2001, 368-376
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TRENDS in Pharmacological Sciences Vol.22 No.8 August 2001, 396