GPCR Signaling

1
GPCR Signaling
Maribissen Gutkind, 2001. G-protein coupled
receptors and signaling networks emerging
paradigms. Trend Pharm. Sci. 22368-376. Luttrel,
et al., 1999. Regulation of tyrosine kinase
cacades by G protein coupled receptors. Curr.
Opin.Cell Biol. 11177-183. Schonberg, T, et al.,
1999. Structural basis of G protein-coupled
receptor function. Mol. Cell. Endocrin.
151181-193. Hamm, H. 1998. The many faces of G
protein signaling. JBC 273669-672. Ji et al.,
1998. G protein coupled receptors I. Diversity of
receptor-ligand interactions. JBC
27317299-17302. Gether and Koblikas, 1998. G
protein coupled receptors II. Mechansim of
agonist actiavtion. JBC 27317979-17982. Lefkowitz
, RJ. 1998. G protein coupled receptors III New
roles for receptor kinases and b-arrestins in
receptor signaling and desensitization. JBC
27318677. Gutkind, S. 1998. The pathways
connecting G protien coupled receptors to the
nucleus through divergent mitogen-activated
protein kinase cascades. JBC 2731839. Fukuhara
et al., 2000. Signaling from G p receptors to the
nucleus, text.
2
2-D model of GPCR Receptor
Gether Koblikas, 1998. JBC 27317979-17982.
3
Palczewski, et al., 2000. Crystal structure of
Rhodopsin Science 289739-745.
4
Gutkind, S. 1998. JBC 231839-1842.
5
GPCR Action
6
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7
G protein Subunits
Hamm, 1998. JBC 273669
Silver Ga subunit Magenta bound nucleotides A,
GTPgS B, GDP Gb contact sites Pink, polar
residues yellow, hydrophobic residues blue,
basic residues red, acidic residues
G gamma
Gbeta
8
G proten interactions with Rhodopsin and
membrane lipid bilayer
Orange loops in receptor that interact with G
protein Blue Galpha Pink G beta Dark blue G
gamma Magenta Bound GDP Red receptor contact
sites
9
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10
Activation of the beta adrenergic receptor by
Gsalpha
11
Adenylyl Cyclase
Binding sites for Gsalpha, black Gialpha,
blue Gbg, yellow
Hurley, 1999. JBC 2747599.
12
Hormone induced activation and inhibition of
Adenylate cyclase
13
Synthesis and degredation of cAMP
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cAMP activates protein kinase A
15
cAMP activates Protein kinase A, which
phosphorylates CREB protein and initiates gene
transcription.
16
Fig. 15-29
Inositol phospholipid signaling
17
Who's who of phosphoinositide signaling
PI Phosphoinositide PIC
Phosphoinositidase C PI3-Kinase (PI3K)
Phosphoinositide 3-kinase PtdIns (PtdI, PI)
Phosphatidylinositol PtdIns(3)P (PtInsP, PIP)
Phosphatidylinositol 3-phosphate
PtdIns(4,5)P2 (PI(4,5)P2, PIP2)
Phosphatidylinositol (4,5)-bis
phosphate PtdIns(3,4,5) P3 (PI(3,4,5)P3, PIP3)
Phosphatidylinositol (3,4,5)- phosphate Ins(1,
4)P2 (IP2) Inositol (1,4)
bisphosphate Ins(1,4,5)P3 (IP3) Inositol
(1,4,5) trisphosphate DAG
Diacylglycerol PLC Phospholipase C
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Hydrolysis of PIP2
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IP3 opens calcium channels on ER
20
Elevation of cytosolic Calcium via the inositol
phospholipid signaling pathway
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Fig. 15-32
Activation of gene transcription by PKC
22
11 PKC isozymes fall into 3 groups 1.     
Conventional (a, b, b and g) Activated by DG and
Ca2 2.      Novel (d, e, h, q, m) Activated by
DG not Ca2 3. Atypical (l , z) DG and Ca2
independent
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Fig. 15-27
Controls on Cytosolic Calcium
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Active Calcium/Calmodulin binds to target proteins
25
GPCR signaling crosstalk
26
Fukuhara, et al. 2000. Signaling from G
protien-coupled receptors to the nucleus. From
signaling networks and cell cycle control The
molecular basis of cancer and other diseases, Ed.
JS Gutkind, Humana Press, NJ.
27
Maribissen Gutkind, 2001. G-protein coupled
receptors and signaling networks emerging
paradigms. Trend Pharm. Sci. 22368-376.
28
GPCR regulation of c-jun expression
29
(No Transcript)
30
ThrombinR
LPAR
G13
G12
RhoGEF
Rho.GTP
Rho.GDP
SRE.L
31
G protein-coupled receptor kinase and arrestin in
receptor desensitization
32
Miller Lefkowitz, 2001. Expanding roles for
b-arrestins as scaffolds and adaptors in GPCR
signaling and trafficking. Curr. Opin. Cell Biol.
13139-145.