gastrointestinal hormone receptors


Summary: Cell surface proteins that bind gastrointestinal hormones with high affinity and trigger intracellular changes influencing the behavior of cells. Most gastrointestinal hormones also act as neurotransmitters so these receptors are also present in the central and peripheral nervous systems.

Top Publications

  1. Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8:738-42 pubmed
    ..Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs. ..
  2. Saxena R, Hivert M, Langenberg C, Tanaka T, Pankow J, Vollenweider P, et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet. 2010;42:142-8 pubmed publisher
    ..Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)). ..
  3. Flatt P. Dorothy Hodgkin Lecture 2008. Gastric inhibitory polypeptide (GIP) revisited: a new therapeutic target for obesity-diabetes?. Diabet Med. 2008;25:759-64 pubmed publisher
  4. McClean P, Irwin N, Cassidy R, Holst J, Gault V, Flatt P. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Endocrinol Metab. 2007;293:E1746-55 pubmed
    ..These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet. ..
  5. Shu L, Matveyenko A, Kerr Conte J, Cho J, McIntosh C, Maedler K. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet. 2009;18:2388-99 pubmed publisher
    ..Our findings suggest that beta-cell function and survival are regulated through an interplay between TCF7L2 and GLP-1R/GIP-R expression and signaling in T2DM. ..
  6. Nitz I, Fisher E, Weikert C, Burwinkel B, Li Y, Mohlig M, et al. Association analyses of GIP and GIPR polymorphisms with traits of the metabolic syndrome. Mol Nutr Food Res. 2007;51:1046-52 pubmed
    ..03). In conclusion, we identified a common splice site mutation (rs2291726) of the GIP gene which results in a truncated protein and provide preliminary evidence for an association of the heterozygous GIPR Glu354Gln genotype with CVD. ..
  7. Antonini S, N Diaye N, Baldacchino V, Hamet P, Tremblay J, Lacroix A. Analysis of the putative regulatory region of the gastric inhibitory polypeptide receptor gene in food-dependent Cushing's syndrome. J Steroid Biochem Mol Biol. 2004;91:171-7 pubmed
    ..In conclusion, mutations or SNPs in the regulatory region of the GIPR gene are unlikely to underlie GIP-dependent CS. ..
  8. Chao C, Tallman M, Ives K, Townsend C, Hellmich M. Gastrointestinal hormone receptors in primary human colorectal carcinomas. J Surg Res. 2005;129:313-21 pubmed
    ..Importantly, our data provide a rationale for examining of the role of these GI peptide hormones and their cognate receptors in mesenchymal cell biology. ..
  9. Moens K, Heimberg H, Flamez D, Huypens P, Quartier E, Ling Z, et al. Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes. 1996;45:257-61 pubmed
    ..In conclusion, these data show that stimulation of glucagon, GLP-I, and GIP receptors in rat beta-cells causes cAMP production required for insulin release, while adenylate cyclase in alpha-cells is positively regulated by GIP. ..

More Information


  1. Harada N, Yamada Y, Tsukiyama K, Yamada C, Nakamura Y, Mukai E, et al. A novel GIP receptor splice variant influences GIP sensitivity of pancreatic beta-cells in obese mice. Am J Physiol Endocrinol Metab. 2008;294:E61-8 pubmed
    ..05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice. ..
  2. Kubota A, Yamada Y, Hayami T, Yasuda K, Someya Y, Ihara Y, et al. Identification of two missense mutations in the GIP receptor gene: a functional study and association analysis with NIDDM: no evidence of association with Japanese NIDDM subjects. Diabetes. 1996;45:1701-5 pubmed
    ..Association studies show no relationship between NIDDM and either of the two mutations. ..
  3. Hamann J, Eichler W, Hamann D, Kerstens H, Poddighe P, Hoovers J, et al. Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain. J Immunol. 1995;155:1942-50 pubmed
    ..The gene encoding CD97 is localized on chromosome 19 (19p13.12-13.2). ..
  4. Baldacchino V, Oble S, Décarie P, Bourdeau I, Hamet P, Tremblay J, et al. The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing's syndrome. J Mol Endocrinol. 2005;35:61-71 pubmed
    ..This study represents the first step in our understanding of the mechanisms involved in the regulation of the expression of the hGIP-R gene. ..
  5. Yamada Y, Seino Y. Physiology of GIP--a lesson from GIP receptor knockout mice. Horm Metab Res. 2004;36:771-4 pubmed
    ..From these studies, we now know that GIP not only mediates early insulin secretion by acting on pancreatic beta-cells, but also links overnutrition to obesity by acting on adipocytes. ..
  6. Irwin N, McClean P, O Harte F, Gault V, Harriott P, Flatt P. Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice. Diabetologia. 2007;50:1532-40 pubmed
    ..001) compared with those observed in lean controls. These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes. ..
  7. Ishihara T, Nakamura S, Kaziro Y, Takahashi T, Takahashi K, Nagata S. Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J. 1991;10:1635-41 pubmed
    ..A 2.5 kb mRNA coding for the secretin receptor could be detected in NG108-15 cells, and rat heart, stomach and pancreatic tissue. ..
  8. Kaul A. Erythromycin as a prokinetic agent. J Pediatr Gastroenterol Nutr. 2002;34:13-5 pubmed
  9. N Diaye N, Tremblay J, Hamet P, de Herder W, Lacroix A. Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing's syndrome. J Clin Endocrinol Metab. 1998;83:2781-5 pubmed
    ..We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing's syndrome. ..
  10. Usdin T, Mezey E, Button D, Brownstein M, Bonner T. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology. 1993;133:2861-70 pubmed
    ..This suggests that a novel peptide may be present in the brain. ..
  11. Tseng C, Kieffer T, Jarboe L, Usdin T, Wolfe M. 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. 1996;98:2440-5 pubmed
    ..It is concluded that GIP (7-30)-NH2 is a GIP-specific receptor antagonist and that GIP plays a dominant role in mediating postprandial insulin release. ..
  12. Lynn F, Pamir N, Ng E, McIntosh C, Kieffer T, Pederson R. Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes. 2001;50:1004-11 pubmed
    ..These data suggest that the decreased effectiveness of GIP in the VDF rat and in type 2 diabetes may be a result of a decreased receptor expression in the islet. ..
  13. Piteau S, Olver A, Kim S, Winter K, Pospisilik J, Lynn F, et al. Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochem Biophys Res Commun. 2007;362:1007-12 pubmed
    ..These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity. ..
  14. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, et al. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A. 1999;96:14843-7 pubmed
  15. Lynn F, Thompson S, Pospisilik J, Ehses J, Hinke S, Pamir N, et al. A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. FASEB J. 2003;17:91-3 pubmed
  16. Xu G, Kaneto H, Laybutt D, Duvivier Kali V, Trivedi N, Suzuma K, et al. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007;56:1551-8 pubmed
    ..Taken together, GLP-1 and GIP receptor expression is decreased with chronic hyperglycemia, and this decrease likely contributes to the impaired incretin effects found in diabetes. ..
  17. Tabo M, Komatsu R, Honda M, Itoh M, Kimura K. Cardiovascular safety profile of MA-2029, a novel motilin receptor antagonist. J Toxicol Sci. 2008;33:631-9 pubmed
    ..In conclusion, MA-2029 is a novel drug highly expected for the treatment of IBS with lower cardiovascular risk than cisapride. ..
  18. Westaway S, Brown S, Conway E, Heightman T, Johnson C, Lapsley K, et al. The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor. Bioorg Med Chem Lett. 2008;18:6429-36 pubmed publisher
    ..Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent. ..
  19. Holtmann M, Hadac E, Miller L. Critical contributions of amino-terminal extracellular domains in agonist binding and activation of secretin and vasoactive intestinal polypeptide receptors. Studies of chimeric receptors. J Biol Chem. 1995;270:14394-8 pubmed
    ..Thus, the amino terminus of secretin and VIP receptors plays a key role in agonist recognition and responsiveness, with the first loop playing a critical complementary role for the secretin receptor. ..
  20. Meuth Metzinger V, Philouze Rome V, Metzinger L, Gespach C, Guilloteau P. Differential activation of adenylate cyclase by secretin and VIP receptors in the calf pancreas. Pancreas. 2005;31:174-81 pubmed
    ..Calf pancreatic SEC-Rs are coexpressed with VIP-2 receptors that we previously identified by ligand binding and cross-linking experiments. ..
  21. Ehses J, Lee S, Pederson R, McIntosh C. 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. 2001;276:23667-73 pubmed
    ..Finally, stimulation of GIP-mediated AA production was shown to be mediated via a Ca(2+)-independent phospholipase A(2). Arachidonic acid is therefore a new component of GIP-mediated signal transduction in the beta-cell. ..
  22. Dong M, Miller L. Molecular approximation between residue 10 of secretin and its receptor demonstrated by photoaffinity labeling. Ann N Y Acad Sci. 2006;1070:243-7 pubmed
    ..These data provide an important constraint for modeling the agonist-bound G protein-coupled secretin receptor and should add substantially to our current understanding of the molecular basis of ligand binding of this important receptor. ..
  23. Huang J, Zhou H, Mahavadi S, Sriwai W, Lyall V, Murthy K. Signaling pathways mediating gastrointestinal smooth muscle contraction and MLC20 phosphorylation by motilin receptors. Am J Physiol Gastrointest Liver Physiol. 2005;288:G23-31 pubmed
  24. Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovci A, et al. Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest. 2004;113:635-45 pubmed
  25. Markovic D, Grammatopoulos D. Focus on the splicing of secretin GPCRs transmembrane-domain 7. Trends Biochem Sci. 2009;34:443-52 pubmed publisher
    ..Do the "TMD7-short" receptor variants have a role as novel regulators of GPCR signallng and, if so, what are the implications for hormonal actions and physiology? ..
  26. Yamada Y. [Incretin and bone]. Clin Calcium. 2009;19:1312-7 pubmed publisher
    ..GIP intermittently stimulates osteoblasts and GLP-1 suppresses osteoclasts through a calcitonin-dependent pathway to increase the bone volume. ..
  27. Shimura S, Sasaki T, Ikeda K, Sasaki H, Takishima T. VIP augments cholinergic-induced glycoconjugate secretion in tracheal submucosal glands. J Appl Physiol (1985). 1988;65:2537-44 pubmed
    ..These results indicate that VIP induces mucus glycoprotein release from secretory cells and also that it potentiates the secretion induced by cholinergic stimulation. ..
  28. Irwin N, Flatt P. Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. Diabetologia. 2009;52:1724-31 pubmed publisher
    ..Emerging evidence also suggests that rapid cure of diabetes in grossly obese patients undergoing bypass surgery is mediated, in part, by surgical removal of GIP-secreting K-cells in the upper small intestine. ..
  29. Mehta B, Munir K. Does the MMR vaccine and secretin or its receptor share an antigenic epitope?. Med Hypotheses. 2003;60:650-3 pubmed
    ..These hypothesized events can only occur if the MMR vaccine shares antigenic determinants that resemble secretin or any of its receptor types and remains to be studied. ..
  30. Johnson S, Gunnet J, Moore J, Miller W, Wines P, Rivero R, et al. Synthesis and SAR of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives as non-peptidic motilin receptor antagonists. Bioorg Med Chem Lett. 2006;16:3362-6 pubmed
    ..Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series. ..
  31. Harmar A. Clinical endocrinology and metabolism. Receptors for gut peptides. Best Pract Res Clin Endocrinol Metab. 2004;18:463-75 pubmed
    ..Other peptides may have developmental roles: for example, disruption of endothelin-3 signalling prevents the normal development of the enteric nervous system and contributes to the pathogenesis of Hirschsprung disease. ..
  32. Svoboda M, Ciccarelli E, Tastenoy M, Robberecht P, Christophe J. A cDNA construct allowing the expression of rat hepatic glucagon receptors. Biochem Biophys Res Commun. 1993;192:135-42 pubmed
    ..This demonstrated that the receptor previously described is indeed the rat hepatic glucagon receptor. ..
  33. Oh D, Kim K, Kwon H, Seong J. Cellular and molecular biology of orphan G protein-coupled receptors. Int Rev Cytol. 2006;252:163-218 pubmed
  34. McClean P, Gault V, Irwin N, McCluskey J, Flatt P. Daily administration of the GIP-R antagonist (Pro3)GIP in streptozotocin-induced diabetes suggests that insulin-dependent mechanisms are critical to anti-obesity-diabetes actions of (Pro3)GIP. Diabetes Obes Metab. 2008;10:336-42 pubmed publisher
    ..These data indicate that the beneficial actions of the GIP-R antagonist, (Pro3)GIP, in obesity-diabetes appear to be largely mediated through insulin-dependent mechanisms that merit further investigation. ..
  35. Bollag R, Zhong Q, Ding K, Phillips P, Zhong L, Qin F, et al. Glucose-dependent insulinotropic peptide is an integrative hormone with osteotropic effects. Mol Cell Endocrinol. 2001;177:35-41 pubmed
    ..Thus, GIP plays an integrative role helping coordinate efficient and targeted nutrient absorption and distribution. ..
  36. Tseng C, Zhang X. Role of regulator of G protein signaling in desensitization of the glucose-dependent insulinotropic peptide receptor. Endocrinology. 1998;139:4470-5 pubmed
    ..These results suggest a potential role for RGS2 in modulating GIP-mediated insulin secretion in pancreatic islet cells. ..
  37. Ayala J, Bracy D, Hansotia T, Flock G, Seino Y, Wasserman D, et al. Insulin action in the double incretin receptor knockout mouse. Diabetes. 2008;57:288-97 pubmed
    ..In summary, DIRKO mice exhibit enhanced insulin action compared with wild-type mice when fed a regular chow diet and are protected from high-fat diet-induced obesity and insulin resistance. ..
  38. Kerr B, Irwin N, Flatt P, Gault V. Prolonged GIP receptor activation using stable mini-PEGylated GIP improves glucose homeostasis and beta-cell function in age-related glucose intolerance. Peptides. 2009;30:219-25 pubmed publisher
    ..These data indicate that prolonged activation of the GIP receptor with GIP[mPEG] counters aspects of impaired beta-cell function and age-related glucose intolerance. ..
  39. Karra E, Chandarana K, Batterham R. The role of peptide YY in appetite regulation and obesity. J Physiol. 2009;587:19-25 pubmed publisher
    ..Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3-36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity. ..
  40. Ingelsson E, Langenberg C, Hivert M, Prokopenko I, Lyssenko V, Dupuis J, et al. Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes. 2010;59:1266-75 pubmed publisher
    ..Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. ..
  41. Saad R, Chey W. Recent developments in the therapy of irritable bowel syndrome. Expert Opin Investig Drugs. 2008;17:117-30 pubmed publisher
  42. Gehlert D, Gackenheimer S, Schober D, Beavers L, Gadski R, Burnett J, et al. The neuropeptide Y Y1 receptor selective radioligand, [125I][Leu31,Pro34]peptide YY, is also a high affinity radioligand for human pancreatic polypeptide 1 receptors. Eur J Pharmacol. 1996;318:485-90 pubmed
    ..Therefore, caution needs to be exercised when using Pro34-analogs to define the neuropeptide Y Y1 receptor in vivo and using tissue preparations. ..
  43. Matsumoto M, Nomura T, Momose K, Ikeda Y, Kondou Y, Akiho H, et al. Inactivation of a novel neuropeptide Y/peptide YY receptor gene in primate species. J Biol Chem. 1996;271:27217-20 pubmed
    ..Interestingly, despite its inactivation in humans, the transcripts were abundantly detected in the heart and skeletal muscle, suggesting a novel function of the human gene. ..
  44. Long S, Berna M, Thill M, Pace A, Pradhan T, Hoffmann K, et al. Secretin-receptor and secretin-receptor-variant expression in gastrinomas: correlation with clinical and tumoral features and secretin and calcium provocative test results. J Clin Endocrinol Metab. 2007;92:4394-402 pubmed
  45. Dong M, Hosohata K, Pinon D, Muthukumaraswamy N, Miller L. Differential spatial approximation between secretin and its receptor residues in active and inactive conformations demonstrated by photoaffinity labeling. Mol Endocrinol. 2006;20:1688-98 pubmed
  46. Korolkiewicz R, Sliwinski W, Rekowski P, Szyk A, Mucha P, Konstanski Z, et al. Lysine14galanin(1-15)-NH2: a partial agonist at galanin receptors in rat isolated gastric fundus. Pharmacology. 1997;55:179-84 pubmed
  47. Nguyen T. Peptide T from human immunodeficiency virus envelope does not interact with hepatic, intestinal and colonic vasoactive intestinal peptide (VIP) receptors. Peptides. 1988;9:425-8 pubmed
    ..These observations would also exclude any pathophysiologic effect caused by the crossreactivity of peptide T or its analogues and these VIP receptors. ..
  48. Harikumar K, Hosohata K, Pinon D, Miller L. Use of probes with fluorescence indicator distributed throughout the pharmacophore to examine the peptide agonist-binding environment of the family B G protein-coupled secretin receptor. J Biol Chem. 2006;281:2543-50 pubmed
    ..Combining the fluorescence data with photoaffinity labeling data provides insights into the conformation and dynamics of a natural peptide ligand docked to a Family B G protein-coupled receptor. ..
  49. Holliday N, Lam C, Tough I, Cox H. Role of the C terminus in neuropeptide Y Y1 receptor desensitization and internalization. Mol Pharmacol. 2005;67:655-64 pubmed
    ..However, additional beta-arrestin-independent mechanisms control Y1 receptor trafficking under basal conditions. ..
  50. Tonini M, De Giorgio R, De Ponti F. Progress with novel pharmacological strategies for gastro-oesophageal reflux disease. Drugs. 2004;64:347-61 pubmed
    ..A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy. ..
  51. Hinke S, Manhart S, Kühn Wache K, Nian C, Demuth H, Pederson R, et al. [Ser2]- and [SerP2] incretin analogs: comparison of dipeptidyl peptidase IV resistance and biological activities in vitro and in vivo. J Biol Chem. 2004;279:3998-4006 pubmed
    ..Hence, Ser(P)2-modified incretins present as novel glucose-lowering agents. ..
  52. O Harte F, Gault V, Parker J, Harriott P, Mooney M, Bailey C, et al. Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP. Diabetologia. 2002;45:1281-91 pubmed
  53. McIntosh C, Bremsak I, Lynn F, Gill R, Hinke S, Gelling R, et al. Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin. Endocrinology. 1999;140:398-404 pubmed