“…CCK2R is highly expressed not only in the stomach and the gastrointestinal tract but also in the heart, brain, and kidney 8, 10, 41. Consequently, gastrin is thought to mediate its biological effects primarily through CCK2R, which is a 7‐transmembrane domain G protein–coupled receptor 42. A study suggested that CCK2R antagonists have a protective effect against cerebral ischemia 18.…”
BackgroundIschemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI.Methods and ResultsAdult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes.ConclusionsThese results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.
“…CCK2R is highly expressed not only in the stomach and the gastrointestinal tract but also in the heart, brain, and kidney 8, 10, 41. Consequently, gastrin is thought to mediate its biological effects primarily through CCK2R, which is a 7‐transmembrane domain G protein–coupled receptor 42. A study suggested that CCK2R antagonists have a protective effect against cerebral ischemia 18.…”
BackgroundIschemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI.Methods and ResultsAdult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes.ConclusionsThese results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.
“…Several binding sites for ligand binding to CCK2 receptor have been identified in mutagenesis studies (Fig. 2) (Foucaud et al 2008). Both the C-terminal phenylalanine of the CCK8 peptide and the tryptophan are located in a hydrophobic/aromatic pocket with residues from different transmembrane helices.…”
Section: Cck and Cck Receptorsmentioning
confidence: 99%
“…The sulfate of CCK8 binds to the receptor by two hydrogen bonds with Arg57 and Tyr61 in helix 1.Fig. 2Serpentine representation of human CCK2R (Foucaud et al 2008). Amino acids of the binding and/or activation site are marked and numbered (reprinted from Foucaud et al (2008) with permission of Elsevier)…”
Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH2 in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides.
“…For example, functional regions of the neurotensin receptor-1 (NTR1) were identified [5]. As another example, binding modes for endogenous and nonpeptidic ligands of the cholecystokinin receptors CCK1R and CCK2R were studied in great detail [6]. Based on the findings, a mechanism explaining how two very similar non-peptide ligands of CCK2R differing only by the absence or presence of a methyl group display inverse agonism or partial agonism activity, respectively [7].…”
Section: Structure-activity Relationship Of Gut Hormone Gpcrs Using Smentioning
Abstract:Crystallization and determination of the high resolution three-dimensional structure of β2-adrenergic receptor in 2007 was followed by structure elucidation of a number of other receptors, including those for neurotensin and glucagon. These major advances foster the understanding of structure-activity relationship of these receptors and structure-based rational design of new ligands having more predictable activity. At present, structure determination of gut hormone receptors in complex with their ligands (natural, synthetic) and interacting signalling proteins (G-proteins, arrestins...) represents the forthcoming challenge which promise to revolution gut hormone endocrinonology.
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