Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholecystokinin, or CCK, is a 33-amino acid peptide, originally considered a gut hormone, that acts via two subtypes of receptors, named CCK1-R and CCK2-R. CCK, along with its receptors, has been subsequently localized in the central nervous system, where it exerts, among other fuctions, antiorexinogenic actions. In this survey, we describe findings indicating that CCK, similar to other peptides modulating food intake (e.g., neuropeptide Y, leptin, and orexins), is also able to regulate the function of the hypothalamo-pituitary-adrenal axis, acting on both its central and peripheral branches. CCK stimulates aldosterone secretion via specific receptors (CCK1-Rs and CCK2-Rs in rats, and CCK2-Rs in humans) located in zona glomerulosa cells and coupled to the adenylate cyclase-dependent signaling cascade; and enhances glucocorticoid secretion from zona fasciculata-reticularis cells via an indirect mechanism mainly involving the CCK2-R-mediated stimulation of corticotropin-releasing hormone-dependent ACTH release.
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PMID:Cholecystokinin and adrenal-cortex secretion. 1611 77

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
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PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97

Over the last five decades, several neuropeptides have been discovered which subsequently have been found to be highly conserved during evolution, to be widely distributed both in the central and peripheral nervous system and which act as neurotransmitters and/or neuromodulators. In the eye, the first peptide to be explored was substance P which was reported to be present in the retina but also in peripherally innervated tissues of the eye. Substance P is certainly the best characterized peptide which has been found in sensory neurons innervating the eye. Functionally, it has been shown to act trophically on corneal wound healing and to participate in the irritative response in lower mammals, a model for neurogenic inflammation, where it mediates the noncholinergic nonadrenergic contraction of the sphincter muscle. Over the last three decades, the interest has extended to investigate the presence and distribution of other neuropeptides including calcitonin gene-related peptide, vasoactive intestinal polypeptide, neuropeptide Y, pituitary adenylate cyclase-activating polypeptides, cholecystokinin, somatostatin, neuronal nitric oxide, galanin, neurokinin A or secretoneurin and important functional results have been obtained for these peptides. This review focuses on summarizing the current knowledge about neuropeptides in the eye excluding the retina and retinal pigment epithelium and to elucidate their potential functional significance.
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PMID:Peptidergic nerves in the eye, their source and potential pathophysiological relevance. 1687 80

The neurohormonal control of pancreatic exocrine secretion is a complex interaction of multiple pathways involving a large number of gut hormones, neurotransmitters, and neuropeptides. Recent studies have elucidated a role for cholecystokinin in the regulation of bicarbonate and fluid secretion from pancreatic duct cells and suggested that cholecystokinin stimulation of human pancreatic acinar cells is likely regulated by an indirect mechanism of stimulation of afferent neurons. Evidence supports the regulation of potassium channels in rat pancreatic acinar cells by the cyclic AMP-mediated agonist secretin. Mechanisms for the regulation of cholecystokinin and secretin release by releasing factors have also been elucidated. The area postrema has been implicated in the mediation of inhibition of pancreatic secretion by the gut hormones peptide YY and pancreatic polypeptide. The neurotransmitter serotonin has been demonstrated to play a role in acid-induced secretin release and in pancreatic secretion stimulated by luminal factors. The regulation of pancreatic exocrine secretion by purines, nitric oxide, and gamma-aminobutyric acid as well as by the neuropeptides pituitary adenylate cyclase-activating peptide, gastrin-releasing peptide, and substance P is reviewed. The role of the central nervous system in modulating pancreatic secretion is also described. This review highlights the recent advances in knowledge of the neurohormonal regulation of pancreatic exocrine secretion.
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PMID:Neurohormonal control of pancreatic exocrine secretion. 1703 30

Neuroendocrine tumors of the lung are carcinomas characterized by different impact on the patients' prognosis, ranging from relatively indolent, low- to intermediate-grade neoplasms with longer life expectation (i.e., typical and atypical carcinoids) to very aggressive and poorly differentiated neoplasms with dismal prognosis (i.e., large cell neuroendocrine carcinoma and small cell lung cancer). The standard treatment of typical or atypical carcinoids is the complete surgical resection, whereas the role of radio-chemotherapy in a multimodality treatment or for palliation remains controversial. Conversely, high-grade neuroendocrine carcinomas are in primis treated by aggressive combination chemotherapy, deserving surgical resection for uncommon low-stage tumors. Since evidence has been accumulated that neuroendocrine tumors of the lung are supplied with a wide array of peptide receptors detectable on cell membranes by immunohistochemical methods, innovative strategies for diagnosis and radiometabolic therapy have been devised to target these molecules for the correct clinical management of the patients. In this paper, the structural and functional aspects and the clinical applications of the detection of several peptide receptors in pulmonary neuroendocrine tumors will be reviewed, including somatostatin receptors, vasoactive intestinal peptide/pituitary adenylate cyclase activating peptide family receptors, cholecystokinin /gastrin receptors, bombesin/gastrin releasing peptide receptors, neurotensin receptors, substance P receptors, neuroepeptide Y receptors, calcitonin/calcitonin gene-related peptide receptors, atrial natriuretic peptide receptors, glucagon-like-peptide-1 receptors, oxytocin receptors and endothelin receptors. Only a detailed knowledge of the peptide receptor distribution in these tumor types, especially in uncommon neoplasms such as atypical carcinoids and large cell neuroendocrine carcinomas, is pivotal for planning the most adequate interventions for the patients' diagnosis and therapy.
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PMID:Peptide receptors in neuroendocrine tumors of the lung as potential tools for radionuclide diagnosis and therapy. 1704 25

The field of cholecystokinin (CCK) stimulation of exocrine pancreatic secretion has experienced major changes in the recent past. This review attempts to summarize the present status of the field. CCK production in the intestinal I cells, the molecular forms of CCK produced and subsequently circulated in the blood, the presence or absence of CCK receptors on the isolated pancreatic acinar cells and the associated signaling for acinar cell secretion, and the actual circuits and sites of action for CCK regulation of exocrine pancreatic secretion in vivo are reviewed in different animal species with an emphasis on birds, rodents, and humans. Clear differences in the relative importance of neural and direct modes of CCK action on pancreatic acinar cells were identified. Rodents seem to be endowed with both modes of action, whereas in humans the neural mode may predominate. In birds, such as duck, the direct mode needs further assistance from pituitary adenylate cyclase-activating peptide/VIP receptors. However, much further work needs to be directed to the neural mode to map out all sites of CCK action and details of the full circuits, and we foresee a major revival for this field of research in the near future.
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PMID:How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. 1705 97

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

Lung cancer kills approximately 1.3 million citizens in the world annually. The tyrosine kinase inhibitors (TKI) erlotinib and gefitinib are effective anti-tumor agents especially in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. The goal is to increase the potency of TKI in lung cancer patients with wild type EGFR. G protein-coupled receptors (GPCR) transactivate the wild type EGFR in lung cancer cells. The GPCR can be activated by peptide agonists causing phosphatidylinositol turnover or stimulation of adenylylcyclase. Recently, nonpeptide antagonists were found to inhibit the EGFR transactivation caused by peptides. Nonpeptide antagonists for bombesin (BB), neurotensin (NTS) and cholecystokinin (CCK) inhibit lung cancer growth and increase the cytotoxicity of gefitinib. The results suggest that GPCR transactivation of the EGFR may play an important role in cancer cell proliferation.
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PMID:EGFR Transactivation by Peptide G Protein-Coupled Receptors in Cancer. 2556 90

The major endocrine response to stress occurs via activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading ultimately to increases in circulating glucocorticoids, which are essential for the metabolic adaptation to stress. The major players in the HPA axis are the hypothalamic neuropeptide, corticotropin releasing hormone (CRH), the pituitary hormone adrenocorticotropic hormone, and the negative feedback effects of adrenal glucocorticoids. In addition, a number of other neuropeptides, including vasopressin (VP), angiotensin II, oxytocin, pituitary adenylate cyclase activating peptide, orexin and cholecystokinin, and nesfatin can affect HPA axis activity by influencing the expression and secretion of CRH, and also by modulating pituitary corticotroph function or adrenal steroidogenesis. Of these peptides, VP co-secreted with CRH from axonal terminals in the external zone of the median eminence plays a prominent role by potentiating the stimulatory effect of CRH and by increasing the number of pituitary corticotrophs during chronic challenge. Although the precise role and significance of many of these neuropeptides in regulating HPA axis activity requires further investigation, it is likely that they are part of a multifactorial system mediating the fine tuning of HPA axis activity during adaptation to a variety of physiological and stressful conditions.
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PMID:Regulation of the hypothalamic-pituitary-adrenal axis by neuropeptides. 2596 Dec 71

Nutrients regulate the secretion of gut satiety hormones, which is related to the modulation of food intake and blood glucose levels. Calcium-sensing receptor (CaSR) is involved in regulating gut hormone secretion in response to l-amino acids and multivalent cations. Rodents are often used to investigate the effect of nutrients on these hormonal release. However, results obtained using rodent models are difficult to be applied in humans, we used pigs as a model in this study because their physiology is similar to that of humans. In this study, we investigated whether l-Arginine (l-Arg) could induce gut hormones cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) secretion in the porcine duodenum and if so, whether CaSR mediated l-Arg-regulated gut satiety hormone secretion. Our data showed that treatment with 20 and 50 mM l-Arg induced CCK and GIP secretion compared with 0 mM l-Arg. However, treatment with d-Arg (an inactive isomer) failed to elicit this response. The potency of l-Arg to induce CCK and GIP secretion was enhanced in the presence of extracellular Ca²⁺ and CaSR agonist cinacalcet. However, the effect of Arg on CCK and GIP secretion was attenuated by blocking CaSR and its downstream signaling molecules adenylate cyclase (AC) and phospholipase C (PLC). Taken all together, pig duodenum provides an appropriate model to explore the effects of l-Arg on the secretion of the satiety-related gut hormones CCK and GIP and the role of CaSR in this effect. Further investigations are needed to verify the effect of l-Arg on food intake and blood glucose in human study. PRACTICAL APPLICATION: l-Arginine is able to modulate cholecystokinin and glucose-dependent insulinotropic peptide secretion through the CaSR in pig model, which has a potential role in regulating food intake and blood glucose levels.
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PMID:Sensing of L-Arginine by Gut-Expressed Calcium Sensing Receptor Stimulates Gut Satiety Hormones Cholecystokinin and Glucose-Dependent Insulinotropic Peptide Secretion in Pig Model. 3008 39


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