Download - GPCR
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G PROTEIN COUPLED G PROTEIN COUPLED RECEPTORS RECEPTORS
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These are a large family of cell membrane receptors. These are a large family of cell membrane receptors.
These are linked to effectors such as enzyme, channel, carrier These are linked to effectors such as enzyme, channel, carrier proteins for response effectuation. proteins for response effectuation.
All such receptors have a common pattern of structural All such receptors have a common pattern of structural organization. organization.
Molecule has 7 Molecule has 7 αα-helical membrane spanning hydrophobic -helical membrane spanning hydrophobic amino acid segments, which run into 3 extra cellular 3 intra amino acid segments, which run into 3 extra cellular 3 intra cellular loops.cellular loops.
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The agonist binding site is located some were between the helices The agonist binding site is located some were between the helices on the extra cellular face, while another recognition site formed on the extra cellular face, while another recognition site formed by cytosolic segments. by cytosolic segments.
In the inactive state GDP is bound to their exposed domainIn the inactive state GDP is bound to their exposed domain
Displacement of GDP by GTP occurs.Displacement of GDP by GTP occurs.
The active The active αα-subunit carring GTP dissociates from the other two -subunit carring GTP dissociates from the other two subunits and either activates or inhibits the effector.subunits and either activates or inhibits the effector.
ββ-subunits also been shown to modulate certain effectors like -subunits also been shown to modulate certain effectors like adenylylcyclase and phospholipase C.adenylylcyclase and phospholipase C.
The The αα-subunit has GTPase activity. -subunit has GTPase activity.
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There are 3 major effector path ways,through which GPCRs Functions Adenylylcylase (AC) :- cyclic AMP pathway:
Activation of AC
Intracellular accumulation of second messenger cAMP
Protein kinase (PKA)
Alters the functions of many enzymes, ion channels.
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Phospholipase C: IP3-DAG pathway :-
Activation of phospholipase C
Hydrolyses of the membrane phopholipid phosphatidyl inositol 4,5-bis-phosphate
Generate second messenger IP3 and DAG
Protein kinase (PKC )Ca 2+
Modulates Contraction, secretion, metabolism
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Channel regulation :-
Activated G-proteins can also open or close ionic channelsspecipic for Ca2+ or K+ or Na+ with out intervention of cAMP or IP3
Hyper polarization / depolarization
Changes in Physiological responses
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Maribissen & Gutkind, 2001. G-protein coupled receptors and signaling networks: emerging paradigms. Trend Pharm. Sci. 22:368-376.
Luttrel, et al., 1999. Regulation of tyrosine kinase cacades by G protein coupled receptors. Curr. Opin.Cell Biol. 11:177-183.
Schonberg, T, et al., 1999. Structural basis of G protein-coupled receptor function. Mol. Cell. Endocrin. 151:181-193.
Hamm, H. 1998. The many faces of G protein signaling. JBC 273:669-672.
Ji et al., 1998. G protein coupled receptors I. Diversity of receptor-ligand interactions. JBC 273:17299-17302.
Gether and Koblikas, 1998. G protein coupled receptors: II. Mechansim of agonist actiavtion. JBC 273:17979-17982.
Lefkowitz, RJ. 1998. G protein coupled receptors III: New roles for receptor kinases and b-arrestins in receptor signaling and desensitization. JBC 273:18677.
Gutkind, S. 1998. The pathways connecting G protien coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades. JBC 273:1839.
Fukuhara et al., 2000. Signaling from G p receptors to the nucleus, text.
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Gether & Koblikas, 1998. JBC 273:17979-17982.
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Palczewski, et al., 2000. Crystal structure of Rhodopsin
Science 289:739-745.
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Gutkind, S. 1998. JBC 23:1839-1842.
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Hamm, 1998. JBC 273:669
Silver: G subunit
Magenta: bound nucleotides; A, GTPS; B, GDP
G contact sites: Pink, polar residues; yellow, hydrophobic residues; blue, basic residues; red, acidic residues
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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
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Hurley, 1999. JBC 274:7599.
Binding sites for:
Gsalpha, black
Gialpha, blue
Gbg, yellow
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cAMP activates protein kinase A
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cAMP activates
Protein kinase A, which phosphorylates CREB protein and initiates gene transcription.
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Fig. 15-29 Inositol phospholipid signaling
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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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Fig. 15-32
Activation of gene transcription
by PKC
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11 PKC isozymes fall into 3 groups:
1. Conventional ( and ) Activated by DG and Ca2+
2. Novel ( ) Activated by DG not Ca2+
3. Atypical (, DG and Ca2+ independent
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Fig. 15-27 Controls on Cytosolic Calcium
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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.
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Maribissen & Gutkind, 2001. G-protein coupled receptors and signaling networks: emerging paradigms. Trend Pharm. Sci. 22:368-376.
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Miller & Lefkowitz, 2001. Expanding roles for -arrestins as scaffolds and adaptors in GPCR signaling and trafficking. Curr. Opin. Cell Biol. 13:139-145.
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