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GIP receptor

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Target not currently curated in GtoImmuPdb

Target id: 248

Nomenclature: GIP receptor

Family: Glucagon receptor family

Contents:

Gene and Protein Information Click here for help
class B G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 466 19q13.32 GIPR gastric inhibitory polypeptide receptor 20
Mouse 6 460 7 A3 Gipr gastric inhibitory polypeptide receptor
Rat 7 455 1q21 Gipr gastric inhibitory polypeptide receptor 18
Previous and Unofficial Names Click here for help
Gippr | GIP-R
Database Links Click here for help
Specialist databases
GPCRdb gipr_human (Hs), gipr_mouse (Mm), gipr_rat (Rn)
Other databases
Alphafold P48546 (Hs), Q0P543 (Mm), P43219 (Rn)
CATH/Gene3D 4.10.1240.10
ChEMBL Target CHEMBL4383 (Hs), CHEMBL4879457 (Mm), CHEMBL5001 (Rn)
Ensembl Gene ENSG00000010310 (Hs), ENSMUSG00000030406 (Mm), ENSRNOG00000015860 (Rn)
Entrez Gene 2696 (Hs), 381853 (Mm), 25024 (Rn)
Human Protein Atlas ENSG00000010310 (Hs)
KEGG Gene hsa:2696 (Hs), mmu:381853 (Mm), rno:25024 (Rn)
OMIM 137241 (Hs)
Pharos P48546 (Hs)
RefSeq Nucleotide NM_000164 (Hs), NM_001080815 (Mm), NM_012714 (Rn)
RefSeq Protein NP_000155 (Hs), NP_001074284 (Mm), NP_036846 (Rn)
UniProtKB P48546 (Hs), Q0P543 (Mm), P43219 (Rn)
Wikipedia GIPR (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  GIP receptor extracellular domain in complex with its endogenous ligand.
PDB Id:  2QKH
Ligand:  gastric inhibitory polypeptide   This ligand is endogenous
Resolution:  1.9Å
Species:  Human
References:  13
Natural/Endogenous Ligands Click here for help
gastric inhibitory polypeptide {Sp: Human} , gastric inhibitory polypeptide {Sp: Mouse} , gastric inhibitory polypeptide {Sp: Rat}

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
gastric inhibitory polypeptide {Sp: Human} Peptide Ligand is endogenous in the given species Hs Full agonist 8.7 pKd 20
⤷ pKd 8.7 [20]
gastric inhibitory polypeptide {Sp: Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 8.6 pKd 7
⤷ pKd 8.6 [7]
[125I]GIP (human) Peptide Ligand is labelled Ligand is radioactive Rn Full agonist 8.6 pKd 7
⤷ pKd 8.6 (Kd 2.51x10-9 M) [7]
retatrutide Peptide Click here for species-specific activity table Hs Full agonist 10.2 pKi 4
⤷ pKi 10.2 (Ki 5.7x10-11 M) [4]
tirzepatide Peptide Approved drug Click here for species-specific activity table Hs Agonist 9.9 pKi 3
⤷ pKi 9.9 (Ki 1.35x10-10 M) [3]
gastric inhibitory polypeptide {Sp: Human} Peptide Hs Agonist 9.1 pKi 10
⤷ pKi 9.1 (Ki 7.5x10-10 M) [10]
human GIP(1-30)NH2 Peptide Hs Agonist 9.1 pKi 10
⤷ pKi 9.1 (Ki 8.9x10-10 M) [10]
Description: Value derived from ligand binding In a competitive binding assay.
retatrutide Peptide Click here for species-specific activity table Hs Full agonist 10.2 pEC50 4
⤷ pEC50 10.2 (EC50 6.4x10-11 M) [4]
Description: Determined in a cAMP assay
gastric inhibitory polypeptide {Sp: Human} Peptide Rn Full agonist 8.6 pIC50 9
⤷ pIC50 8.6 [9]
GIP-(6-30)-amide Peptide Rn Full agonist 8.5 pIC50 9
⤷ pIC50 8.5 [9]
GIP-(7-30) Peptide Rn Partial agonist 6.8 pIC50 9
⤷ pIC50 6.8 [9]
GIP-(10-30) Peptide Rn Partial agonist 6.2 pIC50 9
⤷ pIC50 6.2 [9]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
human GIP(3-30)NH2 Peptide Hs Antagonist 8.6 pKi 10
⤷ pKi 8.6 (Ki 2.3x10-9 M) [10]
human GIP(5-30)NH2 Peptide Hs Antagonist 8.2 pKi 10
⤷ pKi 8.2 (Ki 5.9x10-9 M) [10]
mGIPAnt-1 Peptide Hs Antagonist 8.0 pIC50 1
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [1]
human GIP(3-42)NH2 Peptide Hs Binding 7.7 pIC50 5
⤷ pIC50 7.7 (IC50 2.2x10-8 M) [5]
Description: Binding affinity for the human receptor expressed in COS7 cells.
maridebart cafraglutide Peptide Click here for species-specific activity table Monkey Antagonist 7.6 pIC50 19
⤷ pIC50 7.6 (IC50 2.65x10-8 M) [19]
Description: In vitro potency in GIPR recombinant cells
maridebart cafraglutide Peptide Click here for species-specific activity table Hs Antagonist 7.4 pIC50 19
⤷ pIC50 7.4 (IC50 4.24x10-8 M) [19]
Description: In vitro potency in GIPR recombinant cells
human GIP(3-42)NH2 Peptide Hs Antagonist 6.1 – 7.0 pIC50 5
⤷ pIC50 6.1 – 7.0 (IC50 7.31x10-7 – 9.2x10-8 M) [5]
Description: Measuring in vitro inhibition of native GIP-induced cAMP accumulation at [GIP] of 10 pM and 1 nM.
mGIPAnt-1 Peptide Mm Antagonist 6.6 pIC50 1
⤷ pIC50 6.6 (IC50 2.69x10-7 M) [1]
maridebart cafraglutide Peptide Click here for species-specific activity table Rn Antagonist 6.1 pIC50 19
⤷ pIC50 6.1 (IC50 8.223x10-7 M) [19]
Description: In vitro potency in GIPR recombinant cells
MK-0893 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.0 pIC50 22
⤷ pIC50 6.0 (IC50 1.02x10-6 M) [22]
[Pro3]GIP Peptide Mm Antagonist - - 8
⤷ [8]
View species-specific antagonist tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References: 
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Phospholipase A2 stimulation
References:  6
Tissue Distribution Click here for help
Umbilical, aortic and pulmonary artery endothelial cells.
Species:  Human
Technique:  Southern blot, Western blot
References:  23
Heart tissue.
Species:  Mouse
Technique:  Western blotting.
References:  23
Epidemial fat.
Species:  Rat
Technique:  RT-PCR and RNase protection assay.
References:  11
Bone.
Species:  Rat
Technique:  Western blotting.
References:  2
Brain: highest levels found in the olfactory bulb.
Also in the telencephalon, diencephalon, brainstem and cerebellum.
Species:  Rat
Technique:  RT-PCR.
References:  18
Pancreas, stomach, duodenum, proximal small intestine, fat, adrenal and pituitary.
Not detected in the spleen or liver.
Species:  Rat
Technique:  RT-PCR.
References:  18
Small discrete groups of cells within the pancreas; cardiac endothlium; endothelium of major blood vessels; cells within the bronchioles of the lung (may be endothelial cells); inner layers of the cortex of the adrenals; adipose tissue; weak detection in the epithelium of the stomach and small and large intestines.
Species:  Rat
Technique:  in situ hybridisation.
References:  18
Highest levels in the olfactory bulb and layers 3 and 5 of the cerebral cortex.
Relatively high levels in the ventral and dorsal hippocampus, the mammilary bodies and the medial part of the inferior colliculus.
Moderate levels in the anterior and lateral septum, cortical amygdala, claustrum, subthalamic nucleus, substantia nigra, inferior olive, rostral raphe nuclei, including the linear and dorsal raphe nuclei, and the choroid plexus.
Small regions such as the the area subpostrema and a small group of cells in the frontopolar cortex.
Relatively low levels in the striatum.
Endothelium of large blood vessels within the brain.
Species:  Rat
Technique:  in situ hybridisation.
References:  18
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Measurement of intracellular calcium levels in a calcium reporter cell line expressing the rat GIP receptor. These are HEK 293 cells stably expressing apo-aequorin, which emits light upon calcium binding.
Species:  Rat
Tissue:  HEK 293 cells stably expressing the GIP receptor and apo-aequorin.
Response measured:  Increase in intracellular calcium.
References:  18
Measurement of cAMP levels in CHO-K1 cells transfected with the rat GIP receptor.
Species:  Rat
Tissue:  CHO-K1 cells.
Response measured:  Stimulation of cAMP formation.
References:  21
Measurement of [Ca2+] i in COS-7 transfected with the rat GIP receptor and the Ca2+ indicator fura-2/AM.
Species:  Rat
Tissue:  COS-7 cells transfected with the rat GIP receptor and loaded with a Ca2+ indicator.
Response measured:  Increase in [Ca2+] i.
References:  21
Measurement of glucose-dependent cell proliferation (rate of DNA synthesis) in the rat β-cell line INS-1.
Species:  Rat
Tissue:  β-cell line INS-1 endogenously expressing the GIP receptor.
Response measured:  Glucose-dependent cell proliferation.
References:  15
Determination of the activity of the PKA/CREB signalling cascade by measurement of the phosphorylation of CREB using luciferase as a reporter gene and immunoblotting with an antibody for phosphorylated CREB at Ser133.
Species:  Rat
Tissue:  β-cell line INS-1 endogenously expressing the GIP receptor.
Response measured:  Glucose-dependent rise in CREB phosphorylation.
References:  15
Determination of the activity of the MAPK cascade by measurement of the phosphorylation of the transcription factor Elk-1 using luciferase as a reporter gene and immunoblotting with an antibody for the phosphorylated MAPK.
Species:  Rat
Tissue:  β-cell line INS-1 endogenously expressing the GIP receptor.
Response measured:  Glucose-dependent Elk-1 phosphorylation.
References:  15
Measurement of glycerol release in the mouse cell line, 3T3-L1.
Effect of an AC inhibitor on this glycerol production.
Effect of incubation with insulin on this glycerol production.
Effect of the PI3 kinase inhibitor, wartmannin, on this glycerol release.
Species:  Mouse
Tissue:  3T3-L1 cell line.
Response measured:  Stimulation of glycerol release via AC activation.
Blocked by insulin via PI3 Kinase.
References:  11
Measurement of in cytosolic Ca2+ and cAMP concentrations in the osteosarcoma cell line, SaOS2, in response to GIP.
Species:  Human
Tissue:  SaOS2 cells.
Response measured:  Increase in [Ca2+] and cAMP levels.
References:  2
Measurement of collagen type 1 expression in the osteosarcoma cell line, SaOS2.
Species:  Human
Tissue:  SaOS2 cell line.
Response measured:  Stimulation of collagen type 1 expression.
References:  2
Measurement of alkaline phosphatase (ALP) activity in the human osteosarcoma cell line MG63.
Species:  Human
Tissue:  MG63 cell line.
Response measured:  Increase in ALP activity.
References:  2
Measurement of cAMP levels in LGIPR2 cells stably transfected with the rat GIP receptor.
Species:  Rat
Tissue:  LGIPR2 cells.
Response measured:  Stimulation of cAMP production.
References:  16
Measurement of arachidonic acid eflux from CHO-K1 cells transfected with the rat GIP receptor.
Species:  Rat
Tissue:  CHO-K1 cells.
Response measured:  Increase in arachidonic acid release.
References:  6
Physiological Functions Click here for help
Stimulation of insulin release in fasted anesthetised rats.
Species:  Rat
Tissue:  In vivo.
References:  16
Facilitation of glucose uptake in the small intestine.
Species:  Rat
Tissue:  Small intestine.
References:  17
Stimulation of pancreatic insulin release.
Species:  Rat
Tissue:  Pancreas.
References:  17
Physiological Consequences of Altering Gene Expression Click here for help
GIP receptor knockout mice exhibit higher blood glucose levels with impaired initial insulin response after oral glucose.
Since the GIP receptor appears to be involved in insulin secretion, a defect in this receptor may have a role in the development of diabetes.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  12
GIP receptor knockout mice exhibited a defect in insulin secretion leading to glucose intolerance during oral glucose absorption.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  14
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Giprtm1Yse Giprtm1Yse/Giprtm1Yse
involves: 129P2/Ola * C57BL/6J		 MGI:1352753  MP:0002078 abnormal glucose homeostasis PMID: 10611300 
Giprtm1Thor Giprtm1Thor/Giprtm1Thor
involves: 129P2/OlaHsd * C57BL/6		 MGI:1352753  MP:0002694 abnormal pancreas secretion PMID: 14966573 
Giprtm1Thor|Glp1rtm1Ddr Giprtm1Thor/Giprtm1Thor,Glp1rtm1Ddr/Glp1rtm1Ddr
involves: 129/Sv * 129P2/OlaHsd * C57BL/6		 MGI:1352753  MGI:99571  MP:0002694 abnormal pancreas secretion PMID: 14966573 
Giprtm1Yse Giprtm1Yse/Giprtm1Yse
involves: 129P2/Ola * C57BL/6J		 MGI:1352753  MP:0002727 decreased circulating insulin level PMID: 10611300 
Giprtm1Thor Giprtm1Thor/Giprtm1Thor
involves: 129P2/OlaHsd * C57BL/6		 MGI:1352753  MP:0002727 decreased circulating insulin level PMID: 14966573 
Giprtm1Thor|Glp1rtm1Ddr Giprtm1Thor/Giprtm1Thor,Glp1rtm1Ddr/Glp1rtm1Ddr
involves: 129/Sv * 129P2/OlaHsd * C57BL/6		 MGI:1352753  MGI:99571  MP:0002727 decreased circulating insulin level PMID: 14966573 
Giprtm1Yse Giprtm1Yse/Giprtm1Yse
involves: 129P2/Ola * C57BL/6J		 MGI:1352753  MP:0001559 hyperglycemia PMID: 10611300 
Giprtm1Thor Giprtm1Thor/Giprtm1Thor
involves: 129P2/OlaHsd * C57BL/6		 MGI:1352753  MP:0005293 impaired glucose tolerance PMID: 14966573 
Giprtm1Thor|Glp1rtm1Ddr Giprtm1Thor/Giprtm1Thor,Glp1rtm1Ddr/Glp1rtm1Ddr
involves: 129/Sv * 129P2/OlaHsd * C57BL/6		 MGI:1352753  MGI:99571  MP:0005293 impaired glucose tolerance PMID: 14966573 
Giprtm1Thor Giprtm1Thor/Giprtm1Thor
involves: 129P2/OlaHsd * C57BL/6		 MGI:1352753  MP:0005559 increased circulating glucose level PMID: 14966573 
Giprtm1Thor|Glp1rtm1Ddr Giprtm1Thor/Giprtm1Thor,Glp1rtm1Ddr/Glp1rtm1Ddr
involves: 129/Sv * 129P2/OlaHsd * C57BL/6		 MGI:1352753  MGI:99571  MP:0005559 increased circulating glucose level PMID: 14966573 

References

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1. Boer GA, Hunt JE, Gabe MBN, Windeløv JA, Sparre-Ulrich AH, Hartmann B, Holst JJ, Rosenkilde MM. (2022) Glucose-dependent insulinotropic polypeptide receptor antagonist treatment causes a reduction in weight gain in ovariectomised high fat diet-fed mice. Br J Pharmacol, 179 (18): 4486-4499. [PMID:35710141]

2. Bollag RJ, Zhong Q, Phillips P, Min L, Zhong L, Cameron R, Mulloy AL, Rasmussen H, Qin F, Ding KH, Isales CM. (2000) Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology, 141: 1228-1235. [PMID:10698200]

3. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC et al.. (2018) LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab, 18: 3-14. [PMID:30473097]

4. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK et al.. (2022) LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab, 34 (9): 1234-1247.e9. [PMID:35985340]

5. Deacon CF, Plamboeck A, Rosenkilde MM, de Heer J, Holst JJ. (2006) GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations. Am J Physiol Endocrinol Metab, 291 (3): E468-75. [PMID:16608883]

6. Ehses JA, Lee SS, Pederson RA, McIntosh CH. (2001) A new pathway for glucose-dependent insulinotropic polypeptide (GIP) receptor signaling: evidence for the involvement of phospholipase A2 in GIP-stimulated insulin secretion. J Biol Chem, 276 (26): 23667-73. [PMID:11323439]

7. Gallwitz B, Witt M, Morys-Wortmann C, Fölsch UR, Schmidt WE. (1996) GLP-1/GIP chimeric peptides define the structural requirements for specific ligand-receptor interaction of GLP-1. Regul Pept, 63 (1): 17-22. [PMID:8795084]

8. Gault VA, O'Harte FP, Harriott P, Mooney MH, Green BD, Flatt PR. (2003) Effects of the novel (Pro3)GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin. Diabetologia, 46 (2): 222-30. [PMID:12627321]

9. Gelling RW, Coy DH, Pederson RA, Wheeler MB, Hinke S, Kwan T, McIntosh CH. (1997) GIP(6-30amide) contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro. Regul Pept, 69 (3): 151-4. [PMID:9226399]

10. Hansen LS, Sparre-Ulrich AH, Christensen M, Knop FK, Hartmann B, Holst JJ, Rosenkilde MM. (2016) N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. Br J Pharmacol, 173 (5): 826-38. [PMID:26572091]

11. McIntosh CH, Bremsak I, Lynn FC, Gill R, Hinke SA, Gelling R, Nian C, McKnight G, Jaspers S, Pederson RA. (1999) Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin. Endocrinology, 140 (1): 398-404. [PMID:9886851]

12. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A et al.. (1999) Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA, 96 (26): 14843-7. [PMID:10611300]

13. Parthier C, Kleinschmidt M, Neumann P, Rudolph R, Manhart S, Schlenzig D, Fanghänel J, Rahfeld JU, Demuth HU, Stubbs MT. (2007) Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor. Proc Natl Acad Sci USA, 104 (35): 13942-7. [PMID:17715056]

14. Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovci A, Hansotia T, Drucker DJ, Wollheim C, Burcelin R et al.. (2004) Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest, 113 (4): 635-45. [PMID:14966573]

15. Trümper A, Trümper K, Trusheim H, Arnold R, Göke B, Hörsch D. (2001) Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol, 15 (9): 1559-70. [PMID:11518806]

16. Tseng CC, Kieffer TJ, Jarboe LA, Usdin TB, Wolfe MM. (1996) Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat. J Clin Invest, 98 (11): 2440-5. [PMID:8958204]

17. Tseng CC, Zhang XY, Wolfe MM. (1999) Effect of GIP and GLP-1 antagonists on insulin release in the rat. Am J Physiol, 276 (6): E1049-54. [PMID:10362617]

18. Usdin TB, Bonner TI. (1993) Gastric inhibitory polypeptide receptor, a member of the secretin- vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology, 133: 2861-2870. [PMID:8243312]

19. Véniant MM, Lu SC, Atangan L, Komorowski R, Stanislaus S, Cheng Y, Wu B, Falsey JR, Hager T, Thomas VA et al.. (2024) A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab, 6 (2): 290-303. [PMID:38316982]

20. Volz A, Göke R, Lankat-Buttgereit B, Fehmann HC, Bode HP, Göke B. (1995) Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett, 373 (1): 23-9. [PMID:7589426]

21. Wheeler MB, Gelling RW, McIntosh CH, Georgiou J, Brown JC, Pederson RA. (1995) Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties. Endocrinology, 136 (10): 4629-39. [PMID:7664683]

22. Xiong Y, Guo J, Candelore MR, Liang R, Miller C, Dallas-Yang Q, Jiang G, McCann PE, Qureshi SA, Tong X et al.. (2012) Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes. J Med Chem, 55 (13): 6137-48. [PMID:22708876]

23. Zhong Q, Bollag RJ, Dransfield DT, Gasalla-Herraiz J, Ding KH, Min L, Isales CM. (2000) Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells. Peptides, 21 (9): 1427-32. [PMID:11072131]

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