Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger

Cholecystokinin (CCK) was discovered in 1928 in jejunal extracts as a gallbladder contraction factor. It was later shown to be member of a peptide family, which are all ligands for the CCK(1) and CCK(2) receptors. CCK peptides are known to be synthetized in small intestinal endocrine I-cells and cerebral neurons. But in addition, CCK is expressed in several endocrine glands (pituitary cells, thyroid C-cells, pancreatic islets, the adrenals, and the testes); in peripheral nerves; in cortical and medullary kidney cells; in cardial myocytes; and in cells of the immune system. CCK peptides stimulate pancreatic enzyme secretion and growth, gallbladder contraction, and gut motility, satiety and inhibit acid secretion from the stomach. Moreover, they are major neurotransmitters in the brain and the periphery. CCK peptides also stimulate calcitonin, insulin, and glucagon secretion, and they may act as natriuretic peptides in the kidneys. CCK peptides are derived from proCCK with a C-terminal bioactive YMGWMDFamide sequence, in which the Y-residue is partly O-sulfated. The plasma forms are CCK-58, -33, -22, and -8, whereas the small CCK-8 and -5 are potent neurotransmitters. Over the last decades, CCK expression has also been encountered in tumors (neuroendocrine tumors, cerebral astrocytomas, gliomas, acoustic neuromas, and specific pediatric tumors). Recently, a metastastic islet cell tumor was found to cause a specific CCKoma syndrome, suggesting that circulating CCK may be a useful tumor marker

Acute effects of N-terminal progastrin fragments on gastric acid secretion in man

We previously identified an N‐terminal fragment of progastrin in human antrum and plasma, where it circulates in high concentrations. In this study, we examined the effects of N‐terminal progastrin fragments on gastric acid secretion by infusion in healthy individuals. Increasing doses of progastrin fragment 1‐35 were infused intravenously during constant gastric acid stimulation by gastrin‐17. In addition, the effects of progastrin fragment 1‐35, fragment 6‐35, and fragment 1‐19 on gastrin‐17 stimulated acid secretion were tested. The gastrin‐17 stimulated acid secretion decreased 30% after administration of a high dose of progastrin fragment 1‐35 (P < 0.05). In extension, a 1‐h infusion of fragment 1‐35 also decreased gastric acid output. In contrast, fragment 6‐35 did not affect acid secretion, and a single infusion of gastrin‐17 alone did not reveal fading of gastric acid output during the time course of the experiments. The results show that N‐terminal fragments of progastrin may acutely affect gastrin‐stimulated gastric acid secretion in vivo. Structure‐function analysis suggests that the N‐terminal pentapeptide of progastrin is required for the effect

The Origin and Understanding of the Incretin Concept

Gastrointestinal hormones that stimulate insulin secretion at physiological concentrations are incretins. This concept has recently attracted considerable attention in the wake of drugs developed from the gut hormone GLP-1 (glucagon-like peptide-1) for diabetes therapy. But the renewed enthusiasm has also restricted the concept to just two hormones, GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). The purpose of the present overview is two-fold: First to tell that the incretin concept is far from new. It has a more than a century long history full of ups and downs. Second, that the incretin concept may now have become too narrow. Thus, it is likely that incretin comprises additional gastrointestinal hormones, which interact with GIP and GLP-1 during normal meals containing protein, fat and complex carbohydrates (and not just pure glucose). Such broader incretin concept may stimulate development of novel gut hormone-derived drugs

Plasma chromograninx:Plasma chromogranin A is a marker of death in elderly patients presenting with symptoms of heart failure

Cardiovascular risk assessment remains difficult in elderly patients. We examined whether chromogranin A (CgA) measurement in plasma may be valuable in assessing risk of death in elderly patients with symptoms of heart failure in a primary care setting. A total of 470 patients (mean age 73 years) were followed for 10 years. For CgA plasma measurement, we used a two-step method including a screening test and a confirmative test with plasma pre-treatment with trypsin. Cox multivariable proportional regression and receiver-operating curve (ROC) analyses were used to assess mortality risk. Assessment of cardiovascular mortality during the first 3 years of observation showed that CgA measurement contained useful information with a hazard ratio (HR) of 5.4 (95% CI 1.7–16.4) (CgA confirm). In a multivariate setting, the corresponding HR was 5.9 (95% CI 1.8–19.1). When adding N-terminal proBNP (NT-proBNP) to the model, CgA confirm still possessed prognostic information (HR: 6.1; 95% CI 1.8–20.7). The result for predicting all-cause mortality displayed the same pattern. ROC analyses in comparison to NT-proBNP to identify patients on top of clinical variables at risk of cardiovascular death within 5 years of follow-up showed significant additive value of CgA confirm measurements compared with NT-proBNP and clinical variables. CgA measurement in the plasma of elderly patients with symptoms of heart failure can identify those at increased risk of short- and long-term mortality

Molecular structure and genetic mapping of the mouse gastrin gene

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/117035/1/feb20014579396004309.pd

Cholecystokinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [89]) are activated by the endogenous peptides cholecystokinin-8 (CCK-8), CCK-33, CCK-58 and gastrin (gastrin-17). There are only two distinct subtypes of CCK receptors, CCK1 and CCK2 receptors [63, 123], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK2 receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues

Cholecystokinin receptors in GtoPdb v.2023.1

Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [90]) are activated by the endogenous peptides cholecystokinin-8 (CCK-8), CCK-33, CCK-58 and gastrin (gastrin-17). There are only two distinct subtypes of CCK receptors, CCK1 and CCK2 receptors [64, 124], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK2 receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues