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SECRETIN(15)
RHODOPSIN(701)
GLUTAMATE (15)
FRIZZED/TAS2(24)ADHESION
(24)
(388)βγ
α δ
GLP2RGLP1R
GIPRGCGR
PTHR2PTHR1
GRM6
GRM4
GRM7 GRM8GRM2
GRM3
GRM5GRM1
TAS1R2
GABBR2
GABBR1
SMOH
GRPC6A
TAS1R3TAS1R1FZD1
FZD7FZD2
FZD3
FZD8
FZD6
FZD5FZD10
FZD9FZD4
TAS2R4
TAS2R1TAS2R16
TAS2R13TAS2R14TAS2R10TAS2R3TAS2R9
TAS2R8TAS2R7
TAS2R5GPR60
SSTR1 SSTR3SSTR5
SSTR2GPR8
GPR54
UR2R
GALR1GALR2GALR3MCHR1
MCHR2
GPR7SSTR4
CCR10CXCR5
CXCR3CCR11 CXCR2
CXCR1CXCR6
CCR9CCR7
CXC3R1CCRL2 CCR8
RDC1ADMR
AGTR1AGTRL1
GPR26GPR15GPTH2
AGTR2BDKRB2
BDKRB1SALPR
GPR32FPR1
FPRL2
FPRL1
GPR1C5R2
BLTR2 BLTR
C5R1CMKLR1LGR8
LGR7FSHR
LHCGRTSHR
LGR6
LGR4
LGR5
MRGX2
MRGX1
MRGX3
MRGD
MRGFMRGMAS
MRGX4
HM74
FKSG80
XCR1CCBP2
CCR4CCR1
CCR5CCR2
CCR3
CCR6
GPR59
CASRCALCR
CALCRLCRHR2
VIPR2
VIPR1BAI2
LEC1
LEC2
LEC3EMR2
EMR1CD97
GPR111
GPR115GPR116 GPR112 GPR113
GPR114 NMU1RNTSR2
GHSRMTLR
NPY5R
ADORA1ADORA3
GPR50MTNR1B
MTNR1A
GPR52GPR21
OPN4
RRHOPN3
OPN1SWOPN1LW
OPN1MWADRB3
DRD5DRD1
HTR2CHTR2A
ADRA1DADRA1B
ADRA1AHTR1EHTR1F
HTR1D
HTR7HTR5
HTR1AADRA2A
ADRA2CADRA2B
CHRM4CHRM5
CHRM1DRD2
DRD4TAR4
TAR5TAR3
PTGER1 PTGER2PTGERTBXA2RPTGER3
HTR4
HTR6 TAR1
HRH3
HRH2
HRH4PNR
GPR78
OR1A1OR1D2OR1G1OR3A1
OLFACTORYRECEPTORS
GPR119 GPR26
GPR62GPR61
SREB1SREB2
H963FFA1R
F2RLA
F2RL
2F2
RL3
GPR1
06GPR8
7CY
SLT2
CYSL
T1GP
R17
GPR6
5G2
AGP
R4OG
R1P2Y4P2Y2
P2Y6 GPR80GPR91P2Y5
P2Y9
P2Y1P2Y10
FKSC79GPR92GPR35
GPR55
RGRGPR103PTAFR
GPR18
C3ARP2RY11
GPR62
EB12 GPR101
RE2TRHR
PTGIPP2Y12FKSG7
PTGER4
PTGDRSREB3
GPR57GPR58
MC3DMC5R
ADORA2BMC4R
MC1RMC2R
GPR12
GPR3
CNR2CNR1EDG3
EDG5EDG8 EDG6
EDG2
EDG7
EDNRA
GRPR
ETBRLP1
ETBRLP2 EDNRB
EDG4
GPR6
CCKARCCKBRHCRTR2HCRTR1
NPFF2GNRHRII
GNRHR
AVPR1A
AVPR18OXTR
AVPR2BRS3
NMBR
NMU2RNPY1RGPR97 PPYR1NPY2R
PrRPTACR3
TACR1NPFF1
TACR2 GRP72TAC3RL
GPR110TM7XN1 HE6
EMR3
ETL
BAI1
BAI3SCTR
GHRHR
PACAPCELSR2
CELSR3
CELSR1
CRHR1
Others 9%
Genito Urinary Systemand Sex Hormones
3%
Ophthalmology3%
Women`s Health3%
Immunology3%
Respiratory4%
Gastrointestinal5%
Metabolic Disorders7%
Cardiovascular7% Oncology
16%
CNS40%
G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and are responsible for the transduction of a diverse range of extracellular signals. The range of physiological processes mediated by GPCRs makes them one of the most important classes of proteins for drug discovery.
The study of GPCRs may involve ligand binding, G protein activation, internalization, and downstream second messenger events. Each step of the pathway offers an opportunity to exploit the full therapeutic potential of targeting GPCRs.
Introduction
G protein-dependentsignaling
AC PLCβ ion channel
Arrestin-dependentsignaling (see page 2)
TK MAPK E3ligase
GOPα
β γ
β-arrestin
GPCR
Classic GPCR signaling arises from heterotrimeric G protein dependent activation of membrane-delimited effectors [e.g., adenylyl cyclase (AC), phospholipase C isoforms (PLCβ), and ion channels] that generate intracellular second messengers. In the current model, arrestins function as ligand-regulated scaffolds, linking GPCRs to nontraditional effector pathways [e.g., nonreceptor tyrosine kinases (TK), MAP kinases (MAPK), and E3 ubiquitin ligases]. Because arrestin binding precludes further heterotrimeric G protein coupling, these two signaling “states” of the receptor are mutually exclusive.
G protein-coupled receptor signaling
SECRETIN(15)
RHODOPSIN(701)
GLUTAMATE (15)
FRIZZED/TAS2(24)ADHESION
(24)
(388)βγ
α δ
GLP2RGLP1R
GIPRGCGR
PTHR2PTHR1
GRM6
GRM4
GRM7 GRM8GRM2
GRM3
GRM5GRM1
TAS1R2
GABBR2
GABBR1
SMOH
GRPC6A
TAS1R3TAS1R1FZD1
FZD7FZD2
FZD3
FZD8
FZD6
FZD5FZD10
FZD9FZD4
TAS2R4
TAS2R1TAS2R16
TAS2R13TAS2R14TAS2R10TAS2R3TAS2R9
TAS2R8TAS2R7
TAS2R5GPR60
SSTR1 SSTR3SSTR5
SSTR2GPR8
GPR54
UR2R
GALR1GALR2GALR3MCHR1
MCHR2
GPR7SSTR4
CCR10CXCR5
CXCR3CCR11 CXCR2
CXCR1CXCR6
CCR9CCR7
CXC3R1CCRL2 CCR8
RDC1ADMR
AGTR1AGTRL1
GPR26GPR15GPTH2
AGTR2BDKRB2
BDKRB1SALPR
GPR32FPR1
FPRL2
FPRL1
GPR1C5R2
BLTR2 BLTR
C5R1CMKLR1LGR8
LGR7FSHR
LHCGRTSHR
LGR6
LGR4
LGR5
MRGX2
MRGX1
MRGX3
MRGD
MRGFMRGMAS
MRGX4
HM74
FKSG80
XCR1CCBP2
CCR4CCR1
CCR5CCR2
CCR3
CCR6
GPR59
CASRCALCR
CALCRLCRHR2
VIPR2
VIPR1BAI2
LEC1
LEC2
LEC3EMR2
EMR1CD97
GPR111
GPR115GPR116 GPR112 GPR113
GPR114 NMU1RNTSR2
GHSRMTLR
NPY5R
ADORA1ADORA3
GPR50MTNR1B
MTNR1A
GPR52GPR21
OPN4
RRHOPN3
OPN1SWOPN1LW
OPN1MWADRB3
DRD5DRD1
HTR2CHTR2A
ADRA1DADRA1B
ADRA1AHTR1EHTR1F
HTR1D
HTR7HTR5
HTR1AADRA2A
ADRA2CADRA2B
CHRM4CHRM5
CHRM1DRD2
DRD4TAR4
TAR5TAR3
PTGER1 PTGER2PTGERTBXA2RPTGER3
HTR4
HTR6 TAR1
HRH3
HRH2
HRH4PNR
GPR78
OR1A1OR1D2OR1G1OR3A1
OLFACTORYRECEPTORS
GPR119 GPR26
GPR62GPR61
SREB1SREB2
H963FFA1R
F2RLA
F2RL
2F2
RL3
GPR1
06GPR8
7CY
SLT2
CYSL
T1GP
R17
GPR6
5G2
AGP
R4OG
R1P2Y4P2Y2
P2Y6 GPR80GPR91P2Y5
P2Y9
P2Y1P2Y10
FKSC79GPR92GPR35
GPR55
RGRGPR103PTAFR
GPR18
C3ARP2RY11
GPR62
EB12 GPR101
RE2TRHR
PTGIPP2Y12FKSG7
PTGER4
PTGDRSREB3
GPR57GPR58
MC3DMC5R
ADORA2BMC4R
MC1RMC2R
GPR12
GPR3
CNR2CNR1EDG3
EDG5EDG8 EDG6
EDG2
EDG7
EDNRA
GRPR
ETBRLP1
ETBRLP2 EDNRB
EDG4
GPR6
CCKARCCKBRHCRTR2HCRTR1
NPFF2GNRHRII
GNRHR
AVPR1A
AVPR18OXTR
AVPR2BRS3
NMBR
NMU2RNPY1RGPR97 PPYR1NPY2R
PrRPTACR3
TACR1NPFF1
TACR2 GRP72TAC3RL
GPR110TM7XN1 HE6
EMR3
ETL
BAI1
BAI3SCTR
GHRHR
PACAPCELSR2
CELSR3
CELSR1
CRHR1
Others 9%
Genito Urinary Systemand Sex Hormones
3%
Ophthalmology3%
Women`s Health3%
Immunology3%
Respiratory4%
Gastrointestinal5%
Metabolic Disorders7%
Cardiovascular7% Oncology
16%
CNS40%
GPCRs Super-Family 375 GPCR Drug Targets, 225 with Known Ligands, 150 Orphan Targets
The stabilization of unique GPCR conformations is determined by the molecular properties of the agonist, receptor and signalling proteins (in this case the different G proteins G1, G2, G3 and β-arrestin) at the level of the ternary complex.
The strength of the GPCR signal imparted to the cell by agonists is determined by the molecular parameters governing the direct activation of the receptor and the allosteric effect of the ligand on endogenous receptor affinity. This signal can then interact with other pathways in the cell and the total cellular response thus becomes the result of an amalgam of stimuli.
Under these circumstances, the stoichiometry of the GPCR signalling components in the cell can change the nature of the cellular response, making whole-cell responses cell type-dependent.
Allosteric interactions of GPCRsand beta-Arrestin signalling