Class B/2 (Secretin family receptors) (Homo sapiens)

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1610, 33, 35, 60, 6554, 6617, 19, 37, 40, 4723, 5930, 38, 45, 494, 7, 13, 31, 36...5, 5714, 158, 50, 52205, 17, 5511, 24, 28251, 5644, 61, 642, 12, 18, 27, 34...6, 9, 22643, 26, 5129, 32cytosolGLP2R:GCG(146-178)GNB3 WNT9A CALCR UCN(83-122) CGRP receptorPTH1R,PTH2R ligandsWNT7B(32-349) CRHBPCALCR:CALCA(83-119)ADCYAP1(132-169) CD55:CD97SMOWNT5A ADM(95-146) GCG(53-81)GNG2 GLP2R FZD2 PTCH1 mature GLP-1WNT9B GNG5 RAMP2 CRH,UCN,UCN2,UCN3CHOL-N-palmitoyl-L-cysteine-SHH(24-197) CRHBP RAMP2 GNGT1 ADCYAP1 peptidesGHRHR RAMP1 VIPR2 GNB3 CALCR FZD3 WNT11 ArgN-GCG(98-127) FZD6 GNG13 GNG8 WNT10B CRHBP:CRHCALCA(83-119) VIPR2 GCGRIAPP(34-70)CD97 GNGT1 FZD9 SCT Patched:HedgehogGLP-1:GLP-1R:Heterotrimeric G(s):GDPWNT8A FZD7 ADCYAP1(132-169) CHOL-N-palmitoyl-L-cysteine-IHH(28-202) WNT10A GLP1R FZD7 Frizzled receptorsGDP WNT8A FZD6 GNG12 RAMP3 CGRP ligandsCALCA(83-119)UCN2 UCN2 ADM,ADM2WNT1 UCN3 GNG4 PTH1R RAMP3 EMR1 GNG10 GNAS2 AdrenomedullinreceptorCRHR2-2:CRH,UCN,UCN2,UCN3PTH2R AMY1-3WNT2 GCG(53-81) WNT2B(?-391) PTCH2 WNT9B GIPRGNG7 EMR3(22-652) PTCH1,PTCH2GNAS1 FZD1 IAPP(34-70) CRHR1, CRHR2-1CALCRL PTH2R GCGR GNG5 PTHLH CD97 GLP2RGIPR CRH PTHLH GCG(146-178) PTCH1,PTCH2:SMOEGF-7TMs:CHSGLP-1 (7-37) CRHR2-1 RAMP2 GNB1 ADM(95-146) WNT7A CRHR2-2GCG(146-178)WNT10B WNT5A WNT8B ADCYAP1(82-129) CRHR1,CRHR2-1:CRH,UCNPTH2(62-100) PTH GNB4 ADCYAP1(132-158) EMR1 PTH1R,PTH2R:PTH1R,PTH2R ligandsPTCH2 CRHR2-1 GIPR:GIP(52-93)PTH1R,PTH2RGNB2 GNAS1 SMO GNG13 WNT8B CHS CRHGLP-1 (7-37) WNT3A RAMP3 FZD4 PTCH1 CD55 CGRP1 receptor:CGRPSCTR CRH,UCNGNG10 WNT4 UCN(83-122) VIPR1 ADCYAP1R1RAMP2 SCTR:SCTFZD5 GNG4 FZD9 GLP-1R:Heterotrimeric G(s):GDPADM2(19-153) GDP VIP(125-152) CALCA(83-119) FZD4 WNTsWNT3 UCN(83-122) GLP1R GHRHRCD55ADCYAP1R1 PTH EMR2 VIPR1,VIPR2:VIP(125-152)GNB5 WNT7B(32-349) WNT9A WNT1 G alpha (q)signalling eventsRAMP1 EMR3(22-652) CRH GNB1 VIP(125-152)GNG11 CALCRFZD3 RAMP1 WNT6 CALCRL CALCB(82-118) GNG12 WNT16 CALCRL Frizzledreceptors:WNTsCRH FZD10 GNGT2 GIP(52-93)CHSArgN-GCG(98-127) CALCR GNG3 GNG7 ADM2(19-153) CD97WNT10A FZD8 WNT7A WNT16 CRHR2-2 EGF-7TMsGNB4 FZD10 PTCH1 GCGR:GCG(53-81)WNT3A UCN(83-122) VIPR1,VIPR2PTCH2 G alpha (s)signalling eventsSCTWNT11 ADCYAP1(132-158) Adrenomedullinreceptor:ADM,ADM2PTH2(62-100) VIPR1 FZD2 FZD5 RAMP1 WNT3 AMY1-3:IAPP(34-70)GNB2 WNT4 CRH CD97 PTH1R GIP(52-93) UCN3 GNG3 GHRH receptor:GHRHGNAS2 GNG11 GHRH RAMP3 WNT6 GNGT2 CHOL-N-palmitoyl-L-cysteine-DHH(23-198) ADCYAP1R1:ADCYAP1peptidesCALCA(83-119) SCTRADCYAP1(82-129) FZD1 GNB5 WNT2B(?-391) CRHR1 CRH GHRHCALCRL WNT2 CRHR1 GNG8 CALCB(82-118) FZD8 GNG2 EMR2 6321


Description

This family is known as Family B (secretin-receptor family, family 2) G-protein-coupled receptors. Family B GPCRs include secretin, calcitonin, parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide receptors; all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway (Harmar AJ, 2001). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 373080
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jassal, Bijay

Quality Tags

Ontology Terms

 

Bibliography

View all...
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History

View all...
CompareRevisionActionTimeUserComment
101719view16:20, 1 November 2018DeSlOntology Term : 'G protein mediated signaling pathway' added !
101248view11:14, 1 November 2018ReactomeTeamreactome version 66
100787view20:41, 31 October 2018ReactomeTeamreactome version 65
100329view19:18, 31 October 2018ReactomeTeamreactome version 64
100269view16:57, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADCYAP1 peptidesComplexR-HSA-420080 (Reactome)
ADCYAP1(132-158) ProteinP18509 (Uniprot-TrEMBL)
ADCYAP1(132-169) ProteinP18509 (Uniprot-TrEMBL)
ADCYAP1(82-129) ProteinP18509 (Uniprot-TrEMBL)
ADCYAP1R1 ProteinP41586 (Uniprot-TrEMBL)
ADCYAP1R1:ADCYAP1 peptidesComplexR-HSA-420103 (Reactome)
ADCYAP1R1ProteinP41586 (Uniprot-TrEMBL)
ADM(95-146) ProteinP35318 (Uniprot-TrEMBL)
ADM,ADM2ComplexR-HSA-420061 (Reactome)
ADM2(19-153) ProteinQ7Z4H4 (Uniprot-TrEMBL)
AMY1-3:IAPP(34-70)ComplexR-HSA-420147 (Reactome)
AMY1-3ComplexR-HSA-420237 (Reactome)
Adrenomedullin receptor:ADM,ADM2ComplexR-HSA-420062 (Reactome)
Adrenomedullin receptorComplexR-HSA-420118 (Reactome)
ArgN-GCG(98-127) ProteinP01275 (Uniprot-TrEMBL) The amide group at the C-terminus is not necessary for biological activity.
CALCA(83-119) ProteinP01258 (Uniprot-TrEMBL)
CALCA(83-119) ProteinP06881 (Uniprot-TrEMBL)
CALCA(83-119)ProteinP01258 (Uniprot-TrEMBL)
CALCB(82-118) ProteinP10092 (Uniprot-TrEMBL)
CALCR ProteinP30988 (Uniprot-TrEMBL)
CALCR:CALCA(83-119)ComplexR-HSA-419848 (Reactome)
CALCRL ProteinQ16602 (Uniprot-TrEMBL)
CALCRProteinP30988 (Uniprot-TrEMBL)
CD55 ProteinP08174 (Uniprot-TrEMBL)
CD55:CD97ComplexR-HSA-879676 (Reactome)
CD55ProteinP08174 (Uniprot-TrEMBL)
CD97 ProteinP48960 (Uniprot-TrEMBL)
CD97ProteinP48960 (Uniprot-TrEMBL)
CGRP ligandsComplexR-HSA-419795 (Reactome)
CGRP receptorComplexR-HSA-419782 (Reactome)
CGRP1 receptor:CGRPComplexR-HSA-420236 (Reactome)
CHOL-N-palmitoyl-L-cysteine-DHH(23-198) ProteinO43323 (Uniprot-TrEMBL)
CHOL-N-palmitoyl-L-cysteine-IHH(28-202) ProteinQ14623 (Uniprot-TrEMBL)
CHOL-N-palmitoyl-L-cysteine-SHH(24-197) ProteinQ15465 (Uniprot-TrEMBL)
CHS MetaboliteCHEBI:37397 (ChEBI)
CHSMetaboliteCHEBI:37397 (ChEBI)
CRH ProteinP06850 (Uniprot-TrEMBL)
CRH,UCN,UCN2,UCN3ComplexR-HSA-8937627 (Reactome)
CRH,UCNComplexR-HSA-8937588 (Reactome)
CRHBP ProteinP24387 (Uniprot-TrEMBL)
CRHBP:CRHComplexR-HSA-8937605 (Reactome)
CRHBPProteinP24387 (Uniprot-TrEMBL)
CRHProteinP06850 (Uniprot-TrEMBL)
CRHR1 ProteinP34998 (Uniprot-TrEMBL)
CRHR1, CRHR2-1ComplexR-HSA-8937597 (Reactome)
CRHR1,CRHR2-1:CRH,UCNComplexR-HSA-8937614 (Reactome)
CRHR2-1 ProteinQ13324-1 (Uniprot-TrEMBL)
CRHR2-2 ProteinQ13324-2 (Uniprot-TrEMBL)
CRHR2-2:CRH,UCN,UCN2,UCN3ComplexR-HSA-8937629 (Reactome)
CRHR2-2ProteinQ13324-2 (Uniprot-TrEMBL)
EGF-7TMs:CHSComplexR-HSA-444754 (Reactome)
EGF-7TMsComplexR-HSA-444765 (Reactome)
EMR1 ProteinQ14246 (Uniprot-TrEMBL)
EMR2 ProteinQ9UHX3 (Uniprot-TrEMBL)
EMR3(22-652) ProteinQ9BY15 (Uniprot-TrEMBL)
FZD1 ProteinQ9UP38 (Uniprot-TrEMBL)
FZD10 ProteinQ9ULW2 (Uniprot-TrEMBL)
FZD2 ProteinQ14332 (Uniprot-TrEMBL)
FZD3 ProteinQ9NPG1 (Uniprot-TrEMBL)
FZD4 ProteinQ9ULV1 (Uniprot-TrEMBL)
FZD5 ProteinQ13467 (Uniprot-TrEMBL)
FZD6 ProteinO60353 (Uniprot-TrEMBL)
FZD7 ProteinO75084 (Uniprot-TrEMBL)
FZD8 ProteinQ9H461 (Uniprot-TrEMBL)
FZD9 ProteinO00144 (Uniprot-TrEMBL)
Frizzled receptors:WNTsComplexR-HSA-517468 (Reactome)
Frizzled receptorsComplexR-HSA-517388 (Reactome)
G alpha (q) signalling eventsPathwayR-HSA-416476 (Reactome) The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gq participates in many other signalling events including direct interaction with RhoGEFs that stimulate RhoA activity and inhibition of PI3K. Both in vitro and in vivo, the G-protein Gq seems to be the predominant mediator of the activation of platelets. Moreover, G alpha (q) can stimulate the activation of Burton tyrosine kinase (Ma Y C et al. 1998). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (z) (Soundararajan M et al. 2008).
G alpha (s) signalling eventsPathwayR-HSA-418555 (Reactome) The general function of the G alpha (s) subunit (Gs) is to activate adenylate cyclase (Tesmer et al. 1997), which in turn produces cAMP, leading to the activation of cAMP-dependent protein kinases (often referred to collectively as Protein Kinase A). The signal from the ligand-stimulated GPCR is amplified because the receptor can activate several Gs heterotrimers before it is inactivated. Another downstream effector of G alpha (s) is the protein tyrosine kinase c-Src (Ma et al. 2000).
GCG(146-178) ProteinP01275 (Uniprot-TrEMBL)
GCG(146-178)ProteinP01275 (Uniprot-TrEMBL)
GCG(53-81) ProteinP01275 (Uniprot-TrEMBL)
GCG(53-81)ProteinP01275 (Uniprot-TrEMBL)
GCGR ProteinP47871 (Uniprot-TrEMBL)
GCGR:GCG(53-81)ComplexR-HSA-163627 (Reactome)
GCGRProteinP47871 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GHRH ProteinP01286 (Uniprot-TrEMBL)
GHRH receptor:GHRHComplexR-HSA-420258 (Reactome)
GHRHProteinP01286 (Uniprot-TrEMBL)
GHRHR ProteinQ02643 (Uniprot-TrEMBL)
GHRHRProteinQ02643 (Uniprot-TrEMBL)
GIP(52-93) ProteinP09681 (Uniprot-TrEMBL)
GIP(52-93)ProteinP09681 (Uniprot-TrEMBL)
GIPR ProteinP48546 (Uniprot-TrEMBL)
GIPR:GIP(52-93)ComplexR-HSA-420229 (Reactome)
GIPRProteinP48546 (Uniprot-TrEMBL)
GLP-1 (7-37) ProteinP01275 (Uniprot-TrEMBL)
GLP-1:GLP-1R:Heterotrimeric G(s):GDPComplexR-HSA-422310 (Reactome)
GLP-1R:Heterotrimeric G(s):GDPComplexR-HSA-422314 (Reactome)
GLP1R ProteinP43220 (Uniprot-TrEMBL)
GLP2R ProteinO95838 (Uniprot-TrEMBL)
GLP2R:GCG(146-178)ComplexR-HSA-420087 (Reactome)
GLP2RProteinO95838 (Uniprot-TrEMBL)
GNAS1 ProteinQ5JWF2 (Uniprot-TrEMBL)
GNAS2 ProteinP63092 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (Uniprot-TrEMBL)
IAPP(34-70) ProteinP10997 (Uniprot-TrEMBL)
IAPP(34-70)ProteinP10997 (Uniprot-TrEMBL)
PTCH1 ProteinQ13635 (Uniprot-TrEMBL)
PTCH1,PTCH2:SMOComplexR-HSA-445147 (Reactome)
PTCH1,PTCH2ComplexR-HSA-445134 (Reactome)
PTCH2 ProteinQ9Y6C5 (Uniprot-TrEMBL)
PTH ProteinP01270 (Uniprot-TrEMBL)
PTH1R ProteinQ03431 (Uniprot-TrEMBL)
PTH1R,PTH2R ligandsComplexR-HSA-420569 (Reactome)
PTH1R,PTH2R:PTH1R,PTH2R ligandsComplexR-HSA-420503 (Reactome)
PTH1R,PTH2RComplexR-HSA-420554 (Reactome)
PTH2(62-100) ProteinQ96A98 (Uniprot-TrEMBL)
PTH2R ProteinP49190 (Uniprot-TrEMBL)
PTHLH ProteinP12272 (Uniprot-TrEMBL)
Patched:HedgehogComplexR-HSA-445151 (Reactome)
RAMP1 ProteinO60894 (Uniprot-TrEMBL)
RAMP2 ProteinO60895 (Uniprot-TrEMBL)
RAMP3 ProteinO60896 (Uniprot-TrEMBL)
SCT ProteinP09683 (Uniprot-TrEMBL)
SCTProteinP09683 (Uniprot-TrEMBL)
SCTR ProteinP47872 (Uniprot-TrEMBL)
SCTR:SCTComplexR-HSA-420082 (Reactome)
SCTRProteinP47872 (Uniprot-TrEMBL)
SMO ProteinQ99835 (Uniprot-TrEMBL)
SMOProteinQ99835 (Uniprot-TrEMBL)
UCN(83-122) ProteinP55089 (Uniprot-TrEMBL)
UCN2 ProteinQ96RP3 (Uniprot-TrEMBL)
UCN3 ProteinQ969E3 (Uniprot-TrEMBL)
VIP(125-152) ProteinP01282 (Uniprot-TrEMBL)
VIP(125-152)ProteinP01282 (Uniprot-TrEMBL)
VIPR1 ProteinP32241 (Uniprot-TrEMBL)
VIPR1,VIPR2:VIP(125-152)ComplexR-HSA-420213 (Reactome)
VIPR1,VIPR2ComplexR-HSA-420267 (Reactome)
VIPR2 ProteinP41587 (Uniprot-TrEMBL)
WNT1 ProteinP04628 (Uniprot-TrEMBL)
WNT10A ProteinQ9GZT5 (Uniprot-TrEMBL)
WNT10B ProteinO00744 (Uniprot-TrEMBL)
WNT11 ProteinO96014 (Uniprot-TrEMBL)
WNT16 ProteinQ9UBV4 (Uniprot-TrEMBL)
WNT2 ProteinP09544 (Uniprot-TrEMBL)
WNT2B(?-391) ProteinQ93097 (Uniprot-TrEMBL)
WNT3 ProteinP56703 (Uniprot-TrEMBL)
WNT3A ProteinP56704 (Uniprot-TrEMBL)
WNT4 ProteinP56705 (Uniprot-TrEMBL)
WNT5A ProteinP41221 (Uniprot-TrEMBL)
WNT6 ProteinQ9Y6F9 (Uniprot-TrEMBL)
WNT7A ProteinO00755 (Uniprot-TrEMBL)
WNT7B(32-349) ProteinP56706 (Uniprot-TrEMBL)
WNT8A ProteinQ9H1J5 (Uniprot-TrEMBL)
WNT8B ProteinQ93098 (Uniprot-TrEMBL)
WNT9A ProteinO14904 (Uniprot-TrEMBL)
WNT9B ProteinO14905 (Uniprot-TrEMBL)
WNTsComplexR-HSA-517409 (Reactome)
mature GLP-1ComplexR-HSA-381662 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADCYAP1 peptidesR-HSA-420131 (Reactome)
ADCYAP1R1:ADCYAP1 peptidesArrowR-HSA-420131 (Reactome)
ADCYAP1R1R-HSA-420131 (Reactome)
ADM,ADM2R-HSA-420214 (Reactome)
AMY1-3:IAPP(34-70)ArrowR-HSA-420265 (Reactome)
AMY1-3R-HSA-420265 (Reactome)
Adrenomedullin receptor:ADM,ADM2ArrowR-HSA-420214 (Reactome)
Adrenomedullin receptorR-HSA-420214 (Reactome)
CALCA(83-119)R-HSA-419843 (Reactome)
CALCR:CALCA(83-119)ArrowR-HSA-419843 (Reactome)
CALCRR-HSA-419843 (Reactome)
CD55:CD97ArrowR-HSA-879674 (Reactome)
CD55R-HSA-879674 (Reactome)
CD97R-HSA-879674 (Reactome)
CGRP ligandsR-HSA-420127 (Reactome)
CGRP receptorR-HSA-420127 (Reactome)
CGRP1 receptor:CGRPArrowR-HSA-420127 (Reactome)
CHSR-HSA-444773 (Reactome)
CRH,UCN,UCN2,UCN3R-HSA-8937631 (Reactome)
CRH,UCNR-HSA-420173 (Reactome)
CRHBP:CRHArrowR-HSA-8937613 (Reactome)
CRHBPR-HSA-8937613 (Reactome)
CRHR-HSA-8937613 (Reactome)
CRHR1, CRHR2-1R-HSA-420173 (Reactome)
CRHR1,CRHR2-1:CRH,UCNArrowR-HSA-420173 (Reactome)
CRHR2-2:CRH,UCN,UCN2,UCN3ArrowR-HSA-8937631 (Reactome)
CRHR2-2R-HSA-8937631 (Reactome)
EGF-7TMs:CHSArrowR-HSA-444773 (Reactome)
EGF-7TMsR-HSA-444773 (Reactome)
Frizzled receptors:WNTsArrowR-HSA-201708 (Reactome)
Frizzled receptorsR-HSA-201708 (Reactome)
GCG(146-178)R-HSA-420123 (Reactome)
GCG(53-81)R-HSA-163625 (Reactome)
GCGR:GCG(53-81)ArrowR-HSA-163625 (Reactome)
GCGRR-HSA-163625 (Reactome)
GHRH receptor:GHRHArrowR-HSA-420243 (Reactome)
GHRHR-HSA-420243 (Reactome)
GHRHRR-HSA-420243 (Reactome)
GIP(52-93)R-HSA-420274 (Reactome)
GIPR:GIP(52-93)ArrowR-HSA-420274 (Reactome)
GIPRR-HSA-420274 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GDPArrowR-HSA-381612 (Reactome)
GLP-1R:Heterotrimeric G(s):GDPR-HSA-381612 (Reactome)
GLP2R:GCG(146-178)ArrowR-HSA-420123 (Reactome)
GLP2RR-HSA-420123 (Reactome)
IAPP(34-70)R-HSA-420265 (Reactome)
PTCH1,PTCH2:SMOArrowR-HSA-445124 (Reactome)
PTCH1,PTCH2R-HSA-445124 (Reactome)
PTH1R,PTH2R ligandsR-HSA-420489 (Reactome)
PTH1R,PTH2R:PTH1R,PTH2R ligandsArrowR-HSA-420489 (Reactome)
PTH1R,PTH2RR-HSA-420489 (Reactome)
Patched:HedgehogTBarR-HSA-445124 (Reactome)
R-HSA-163625 (Reactome) Glucagon (Thomsen J et al, 1972) is an important peptide hormone produced by the pancreas. It is released when the glucose level in the blood is low (hypoglycemia), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin. Glucagon, together with glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), are peptide hormones encoded by a single common prohormone precursor, proglucagon.The glucagon receptor (Lok S et al, 1994) plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by coupling to Gs and q, which stimulate adenylyl cyclase and a phosphatidylinositol-calcium second messenger system respectively.
R-HSA-201708 (Reactome) The highly conserved Wnt signaling proteins play critical roles in guiding pattern formation, cell fate decision, and morphogenetic movement during animal development. They bind to the Frizzled (FZD) family of seven-pass transmembrane proteins and initiate at least three different intracellular signaling pathways. Historically they were considered to be family B GPCRs but more recent phylogenetic classifications put them into a class of their own (e.g. Schioth & Fredriksson 2005). FZD members have been demonstrated to signal via Gi/o (Slusarski et al. 1997) but this is not considered to be the primary signaling mechanism for these receptors (Hsieh 2004). Instead they signal through the canonical/beta-catenin pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. The canonical/beta-catenin pathway requires a co-receptor protein known as LDL5 or LDL6 (Tamai et al. 2000).
Most Wnt signaling has been attributed to the activation of FZD receptors but there is evidence of FZD-independent signaling (Mikels & Nusse 2006). Much Wnt research has used indirect evidence to infer the involvement of FZD receptors (e.g. Gazit et al. 1999) but there is some direct evidence of Wnt-FZD binding (Hsieh et al. 1999; Mikels & Nusse 2006).
R-HSA-381612 (Reactome) Glucagon-like Peptide-1 is synthesized in intestinal L-cells in response to the presence of glucose and fatty acids absorbed from the intestine. Most GLP-1 is the GLP-1 (7-36) amidated form; some GLP-1 is the GLP-1 (7-37) form. GLP-1 circulates to the pancreas where it binds the Glucagon-like Peptide-1 Receptor (GLP-1R), a G-protein coupled receptor located on the plasma membrane of beta cells. GLP-1R is a seven-pass transmembrane protein and a member of the B family of GPCRs, which have N-terminal extracellular domains of 100-150 amino acids. GLP-1 interacts with the extracellular N-terminal region of GLP-1R.
R-HSA-419843 (Reactome) The CALC1 gene produces a prepropeptide from which calcitonin (CT) is a cleavage product (Nelkin BD et al, 1984). CT is a polypeptide hormone that is produced in the thyroid gland. It acts to reduce blood calcium, opposing the effects of parathyroid hormone. The CT receptor (Gorn AH et al, 1992) binds CT and mediates its actions. The ligand:receptor complex couples to the G protein alpha s subunit, which stimulates adenylyl cyclase and increases intracellular cAMP levels (Gorn AH et al, 1992).
R-HSA-420123 (Reactome) Glucagon-like peptide 2 (GLP-2) (Drucker DJ 1999) is a 33-aa proglucagon-derived peptide produced by intestinal enteroendocrine cells. GLP-2 stimulates intestinal growth. The effects of GLP-2 are mediated by the GLP2 receptor (Munroe DG et al, 1999), which can couple with G protein alpha s subunit that activates adenylyl cyclase (Koehler JA et al, 2005).
R-HSA-420127 (Reactome) The calcitonin gene-related peptides alpha-CGRP and beta-CGRP (Morris HR et al, 1984, Steenbergh PH et al, 1985 respectively) are members of the calcitonin family of peptides and are produced in both peripheral and central neurons. They are the most potent peptide vasodilators and can function in the transmission of pain. Their effects are mediated by binding to the CGRP1 receptor (CL) (Aiyar N et al, 1996). CGRP receptors are complexes between CL and receptor activity modifying protein 1 (RAMP1) (Kuwasako K et al, 2004). The activity of the receptor is mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which can increase intracellular cAMP levels (Van Valen et al, 1990).
R-HSA-420131 (Reactome) The pituitary adenylate cyclase-activating peptide (PACAP) (Ohkubo S et al, 1992) is a peptide hormone similar to vasoactive intestinal peptide (VIP). PACAP functions as a hypophysiotropic hormone, neurotransmitter and neuromodulator. Three active peptides are cleaved from the precursor protein; PACAP-related peptide, PACAP-27 and PACAP-38. The effects of the PACAP peptides are mediated by the PACAP receptor (Ogi K et al, 1993). This receptor is predominantly expressed in the CNS. The activity of the receptor is mediated by coupling with the G protein alpha s subunit, which stimulates adenylyl cyclase which increases intracellular cAMP levels (Ogi K et al, 1993).
R-HSA-420173 (Reactome) Corticoliberin (CRH, aka corticotropin-releasing factor CRF) is a 41-amino acid amino peptide which, together with CRH-related peptides such as the urocortins (UCNs), play a role in coordinating endocrine, autonomic and behavioural responses to stress. These peptides exert their effects through binding and activation of two class B/Secretin family of GPCRs, CRHR1 and CRHR2 (aka CRFR1 and CRFR2 respectively). The activity of these receptors is mediated by coupling to the G protein alpha s subunit, stimulating adenylyl cyclase which increases intracellular cAMP levels (Donaldson et al. 1996). CRH and UCN bind with highest affinity to both CRHR1 and CRHR2-alpha receptors (Donaldson et al. 1996, Pioszak et al. 2008, Pal et al. 2010).
R-HSA-420202 (Reactome) Secretin (SCT) (Whitmore TE et al, 2000) is a peptide hormone belonging to the glucagon peptide hormone family and is produced in the duodenum. Its primary effect is to regulate the pH of the duodenal contents via the control of gastric acid secretion and buffering with bicarbonate. These effects are mediated by the SCT receptor (Patel DR et al, 1995). The receptor activity is mediated by coupling to G protein alpha s subunits, which stimulate adenylyl cyclase which increases intracellular cAMP levels (Patel DR et al, 1995).
R-HSA-420214 (Reactome) Intermedin (AM2) (Roh J et al, 2004) and adrenomedullin (AM) (Kitamura K et al, 1993) belong to the calcitonin peptide hormone family and are important for cardiovascular and respiratory regulation. The functional adrenomedullin receptor AM1 is composed of the calcitonin gene-related peptide receptor (CGPR) and receptor activity modifying protein 2 (RAMP2) (Kamitani S et al, 1999). AM1 receptor can bind either of these peptide hormones and its activity is mediated by coupling with the G protein alpha s subunit which stimulates adenylyl cyclase and increases intracellular cAMP levels (Aiyar N et al, 2001). The function of the AM2 receptor (formed by the combination of CGPR and RAMP3) is very similar to that of AM1.
R-HSA-420233 (Reactome) Vasoactive intestinal peptide (VIP) (Tsukada T et al, 1985) belongs to the glucagon hormone family and is expressed in many parts of the human body. VIP causes vasodilation, lowers arterial blood pressure, stimulates myocardial muscle contraction and increases glycogenolysis. It also relaxes the smooth muscle of trachea, stomach and gall bladder. The effects of VIP are mediated by the VIP receptors of which there are two, 1 and 2 (Sreedharan SP et al, 1993 and Svodoba M et al, 1994 respectively). The actions of the receptor are mediated by coupling with the G protein alpha s subunit, which stimulates adenylyl cyclase which increases intracellular cAMP levels (Sreedharan SP et al, 1993).
R-HSA-420243 (Reactome) Growth hormone-releasing hormone (GHRH, somatocrinin, growth hormone-releasing factor) (Gubler U et al, 1983) is released from neurosecretory cells in the hypothalamus and along with the inhibitory peptide, somatostatin, mediates the neuroendocrine regulation of pituitary growth hormone synthesis and secretion. The GHRH receptor (Gaylinn BD et al, 1993) is expressed in the pituitary gland and mediates the activity of GHRH. Downstream signalling is mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which increases intracellular cAMP levels (Mayo KE, 1992).
R-HSA-420265 (Reactome) Amylin (islet amyloid polypeptide, diabetes associated peptide) is a 37 amino acid peptide first purified from amyloid deposits in the pancreatic islets of type 2 diabetic patients (Nishi M et al, 1989). It is a product of the islet B-cell, along with insulin and probably has a hormonal role in the regulation of nutrient intake. Amylin receptors are multimeric complexes, formed by CT receptor (Gorn AH et al, 1992) interaction with receptor activity modifying proteins (RAMPs) (McLatchie LM et al, 1998). The CT receptor interacts with the three RAMPs, generating multiple subtypes of amylin receptor (AMY1-3).
R-HSA-420274 (Reactome) Gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic peptide) (Moody AJ et al, 1984) is a member of the secretin family of hormones. It is synthesized and secreted from endocrine cells in the small intestine. GIP induces insulin secretion, which is primarily stimulated by hyperosmolarity of glucose in the duodenum. Gastric inhibitory polypeptide receptors are found on beta-cells in the pancreas (Volz A et al, 1995). Their effects are mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which can increase intracellular cAMP levels (Bollag RJ et al, 2000).
R-HSA-420489 (Reactome) Parathyroid hormone (PTH) (Hendy GN et al, 1981), parathyroid hormone-related protein (PTHrP) (Suva LJ et al, 1987) and tuberoinfundibular peptide of thirty-nine residues (TIP39) (Hansen IA et al, 2002; Della Penna K et al, 2003) are endogenous ligands for the parathyroid hormone 1 and 2 receptors. These peptide hormones play a key role in controlling blood Ca(2+) concentration and endochondral bone formation. PTH1 is the classical PTH receptor 1 (Schipani E et al, 1993; Schneider H et al, 1993) and is expressed in high levels in bone and kidney. It regulates calcium ion homeostasis through activation of adenylate cyclase and phospholipase C. PTH receptor 2 (Usdin TB et al, 1995) is most abundant in brain and testes and potently activated by PTH. The activity of these receptors is mediated by G proteins which activate adenylyl cyclase (Schneider H et al, 1994; Offermanns S et al, 1996; Behar V et al, 1996).
R-HSA-444773 (Reactome) The EGF-TM7 receptors are within the family B Adhesion (LNB) receptor subclass. They are characterised by long N-teminal extracellular domains containing multiple epidermal growth factor (EGF)-like domains. CD97 and EMR2 interact with the glycosaminoglycan chondroitin sulfate (CS).
R-HSA-445124 (Reactome) Smoothened (Smo) is usually classified with family B GPCRs based on homology. There are indications that it can signal via G-proteins Gi and G12/13 (Ruiz-Gomez, 2007) but this role is poorly understood. It's better characterised physiological role is as the transducer of hedgehog (HH) signaling. In this capacity Smo is not acting as a receptor, but as part of a signaling cascade.



The Hedgehog(HH)/Smo signalling pathway was identified as a key component of Drosophila development and subsequently found to be conserved in all meatazoans. Most of the functions attributed to Smo are associated with development such as digit patterning in the chick limb bud and left–right asymmetry of vertebrate embryos. In addition, Smo appears to be involved in homeostasis; deregulated Smo signaling is implicated in tumorogenesis (Ruiz-Gomez, 2007).

The ligand of the 12 transmembrane-domain receptor Patched (Ptc) is Hedgehog(HH) but in the absence of HH, Ptc binds Smo (Stone et al. 1996) which consequently becomes internalised into endosomes, where it associates with Costal-2 (Cos2), and lysosomes, where it is degraded. This 'inactivates' Smo by preventing the formation of an active Smo signaling complex at the plasma membrane. Internalised Smo:Cos2 forms a complex with protein kinase A (PKA), casein kinase I (CKI) glycogen synthase kinase-3 (GSK3) and Cucurbitus interruptus (Ci), a transcriptional regulator, enabling phosphorylation of Ci and subsequent processing to a transcriptional repressor form (CiR). When HH binds to Ptc, it does not bind Smo, allowing Smo to undergo a conformational change, exposing a new surface in its cytoplasmic tail. This causes PKA, CKI and GSK3 to dissociate from Smo:Cos2 complexes, so that Ci is no longer phosphorylated or processed to CiR. Accumulating Smo is phosphorylated instead and assumes a third conformational state. Phosphorylated Smo trafficks to the plasma membrane (Denef et al. 2000) and assembles into a signalling complex that promotes the phosphorylation of Fused (Fu) and Cos2. Phosphorylated Cos2 dissociates from membranes and recruits Fu to Sufu (Suppressor of Fused), which produces the activated form of Ci (CiA), probably through phosphorylation of Sufu (Hooper & Scott, 2005).
R-HSA-879674 (Reactome) CD55 (or Decay Accelerating Factor; DAF) is a member of the regulators of complement activation (RCA) family. It protects host cells from complement system attack by binding to C3b and C4b preventing formation of the membrane attack complex. CD97 is a member of the Adhesion class or LNB subfamily of family B GPCRs, characterized by long N-terminal regions containing domains contain multiple tandem epidermal growth factor (EGF)-like repeats in their N-termini (Foord et al. 2002). CD97 is constitutively expressed on granulocytes and monocytes and is rapidly up-regulated on activated T and B cells. It is known to have many splice forms containing different numbers of EGF domains, consequently binding CD55 with differing affinities. The highest affinity variant has three EGF domains. The leukocyte-restricted expression pattern of CD97, and the presence of both CD97 and CD55 in arthritic joints suggest a possible role in adhesion and signaling within the inflammatory and immune responses (Lin et al. 2001).
R-HSA-8937613 (Reactome) Corticoliberin (CRH, aka corticotropin-releasing factor CRF) is a 41-amino acid amino peptide which, together with CRH-related peptides such as the urocortins (UCNs), play a role in coordinating endocrine, autonomic and behavioural responses to stress. These peptides exert their effects through binding and activation of two class B/Secretin family of GPCRs, CRHR1 and CRHR2 (aka CRFR1 and CRFR2 respectively). The corticotropin-releasing factor-binding protein (CRHBP) can bind to CRH with high affinity, inactivating it. CRHBP is expressed in the brains of all species examined to date but is uniquely expressed in human liver and placenta. In the brain, CRHBP is located in pituitary corticotropes, where it is under positive glucocorticoid control, and is likely to locally modulate CRH-induced ACTH secretion (Behan et al. 1993, Behan et al. 1995).
R-HSA-8937631 (Reactome) Corticoliberin (CRH, aka corticotropin-releasing factor CRF) is a 41-amino acid amino peptide which, together with CRH-related peptides such as the urocortins (UCNs), plays a role in coordinating endocrine, autonomic and behavioral responses to stress. These peptides exert their effects through binding and activation of two class B/Secretin family of GPCRs, CRHR1 and CRHR2 (aka CRFR1 and CRFR2 respectively). The activity of these receptors is mediated by coupling to the G protein alpha s subunit, stimulating adenylyl cyclase which increases intracellular cAMP levels (Donaldson et al. 1996). CRH and UCN bind with highest affinity to both CRHR1 and CRHR2 receptors but CRHR2-beta receptors can also bind UCN2 and UCN3 (Pal et al. 2010).
SCTR-HSA-420202 (Reactome)
SCTR:SCTArrowR-HSA-420202 (Reactome)
SCTRR-HSA-420202 (Reactome)
SMOR-HSA-445124 (Reactome)
VIP(125-152)R-HSA-420233 (Reactome)
VIPR1,VIPR2:VIP(125-152)ArrowR-HSA-420233 (Reactome)
VIPR1,VIPR2R-HSA-420233 (Reactome)
WNTsR-HSA-201708 (Reactome)
mature GLP-1R-HSA-381612 (Reactome)
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