Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide] on membrane potential, whole-cell ATP-sensitive potassium channel (K[ATP]) and Ca2+ currents, cytoplasmic Ca2+ concentration, and exocytosis was explored in single human beta-cells. GLP-1(7-36) amide induced membrane depolarization that was associated with inhibition of whole-cell K(ATP) current. In addition, GLP-1(7-36) amide (and forskolin) produced greater than fourfold potentiation of Ca2+-dependent exocytosis. The latter effect resulted in part (40%) from acceleration of Ca2+ influx through voltage-dependent (L-type) Ca2+ channels. More importantly, GLP-1(7-36) amide (via generation of cyclic AMP and activation of protein kinase A) potentiated exocytosis at a site distal to a rise in the cytoplasmic Ca2+ concentration. Photorelease of caged cAMP produced a two- to threefold potentiation of exocytosis when the cytoplasmic Ca2+ concentrations were clamped at > or =170 nmol/l. The effect of GLP-1(7-36) amide was antagonized by the islet hormone somatostatin. Similar effects on membrane potential, ion conductances, and exocytosis were observed with glucose-dependent insulinotropic polypeptide (GIP), the second major incretin. The present data suggest that the strong insulinotropic action of GLP-1(7-36) amide and GIP in humans results from its interaction with several proximal as well as distal important regulatory steps in the stimulus-secretion coupling.
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PMID:Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. 942 75

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

Insulin secretion by isolated islets of Langerhans from 19 human donors (9 women and 10 men) was studied in vitro to test the hypothesis that human islets contain both the K(ATP) channel-dependent and the K(ATP) channel-independent signaling pathways. The results demonstrated the presence of both of these major pathways of glucose signaling. Thus, insulin secretion was stimulated by high glucose concentrations, by the sulfonylurea tolbutamide, and by a depolarizing concentration of potassium chloride. Diazoxide, which activates the K(ATP) channel, completely blocked the stimulation of release by glucose. Stimulation of insulin release by tolbutamide, which inhibits the K(ATP) channel and depolarizes the beta-cell, and inhibition of glucose-stimulated release by diazoxide, which activates the channel and repolarizes the beta-cell, confirm the involvement of the K(ATP) channel-dependent pathway in glucose signaling. The participation of the K(ATP) channel-independent pathway in the stimulation of insulin release by glucose was demonstrated for the first time in human islets. This was done in two ways. The first method, in the presence of diazoxide, blocked the action of glucose on the K(ATP) channel in combination with a depolarizing concentration of KCl to raise [Ca2+]i. Under these conditions, glucose stimulated insulin release. A second method to demonstrate the involvement of the K(ATP) channel-independent pathway was to close the K(ATP) channels with tolbutamide. Again, with no possibility of further action on the K(ATP) channel, glucose stimulated insulin release. In a final series of experiments, glucose-stimulated insulin release was profoundly inhibited by somatostatin, clonidine, and prostaglandin E2, but not by galanin.
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PMID:Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets. 958 47

The effects of the native somatostatin-14 (SST-14) and of its analog octreotide (OCT) on the activity of protein tyrosine kinases (PTK) in the normal rat anterior pituitary gland, diethylstilbestrol (DES)-induced rat pituitary tumor and murine colonic cancer Colon 38 were studied in vitro. PTK activity was estimated in tissue homogenates using gamma-[32P]ATP and poly (Glu80, Tyr20) as a substrate. It was found that both SST-14 and OCT suppressed the PTK activity in all examined tissues. The suppressive effect was more pronounced in DES-induced pituitary tumor than in normal anterior pituitary gland, and in the former, OCT was more effective than SST-14. In contrast, SST-14 stronger suppressed PTK activity in colonic cancer than OCT. We hypothesize that SST-14 acts on PTK activity in colonic cancer mainly via SSTR-1 subtype of somatostatin receptors.
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PMID:Differential effects of somatostatin and its analog on protein tyrosine kinases activity in the rat pituitary and the murine colonic tumors. 961 Mar 66

The P2X3 receptor subunit, a member of the P2X family of ATP-gated ion channels, is almost exclusively localized in sensory neurons. In the present study, we sought to gain insight into the role of P2X3 and P2X3-containing neurons in sensory transmission, using immunohistochemical approaches. In rat dorsal root ganglia (DRG), P2X3-immunoreactivity (-ir) was observed in small- and medium-sized neurons. Approximately 40% of DRG neuronal profiles in normal rats contained P2X3-ir. In rats that had received neonatal capsaicin treatment, the number of P2X3-positive neurons was decreased by approximately 70%. Analysis of the colocalization of P2X3-ir with cytochemical markers of DRG neurons indicated that approximately 94% of the P2X3-positive neuronal profiles were labelled by isolectin B4 from Bandeiraea simplicifolia, while only 3% contained substance P-ir, and 7% contained somatostatin-ir. In dorsal horn of rat spinal cord, P2X3-ir was observed in the inner portion of lamina II and was reduced subsequent to dorsal rhizotomy, as well as subsequent to neonatal capsaicin treatment. Finally, P2X3-ir accumulated proximal to the site of sciatic nerve ligation, and was seen in nerve fibres in skin and corneal epithelium. In summary, our results suggest that P2X3 is expressed by a functionally heterogeneous population of BSI-B4-binding sensory neurons, and is transported into both central and peripheral processes of these neurons.
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PMID:P2X3 is expressed by DRG neurons that terminate in inner lamina II. 982 60

It has been suggested that muscularis mucosae excitation may augment gastric acid secretion, implying that this muscle should contract to secretagogues or stimulation of its motor innervation. The aim of this study was to characterize in vitro the responses of the muscularis mucosae in the rabbit gastric corpus to substances that modulate acid release and to intrinsic nerve stimulation. Muscularis mucosae from both fundic and antral ends of the corpus had identical mechanical properties, contracted to ACh, ADP, ATP, and histamine but relaxed to vasoactive intestinal polypeptide. Fundic but not antral muscularis mucosae contracted to bombesin and PGE2 and PGF2alpha, whereas adenosine, AMP, CCK, gastrin, secretin, and somatostatin were without effect on any preparation. In both regions electrical field stimulation evoked TTX-sensitive responses consisting of an atropine-resistant contraction followed by an NG-nitro-L-arginine methyl ester- and indomethacin-resistant relaxation. It is concluded from the regional variability in the pharmacological properties of the gastric muscularis mucosae that if its motor activity is linked to acid secretion this would be achieved by a neurally mediated relaxation rather than a paracrine- and/or endocrine-induced alteration in tone.
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PMID:Characteristics of the muscularis mucosae in the acid-secreting region of the rabbit stomach. 1033 12

1. Diadenosine triphosphate (AP3A) and diadenosine tetraphosphate (AP4A) are released by various cells (e.g. platelets and chromaffin cells), and may act as extracellular messengers. In pancreatic B-cells, AP3A and AP4A are inhibitors of the ATP-regulated K+ channels, and glucose increases intracellular levels of both substances. 2. We have studied the effect of exogenous AP3A and AP4A on insulin and glucagon secretion by the perfused rat pancreas. 3. AP3A did not significantly modify insulin or glucagon release, whereas AP4A induced a prompt, short-lived insulin response ( approximately 4 fold higher than basal value; P<0.05) in pancreases perfused at different glucose concentrations (3.2, 5.5 or 9 mM). AP4A-induced insulin release was abolished by somatostatin and by diazoxide. These two substances share the capacity to activate ATP-dependent K+ channels, suggesting that these channels are a potential target for AP4A in the B-cell. 4. AP4A stimulated glucagon release at both 3.2 and 5.5 mM glucose. This effect was abolished by somatostatin. 5. The results suggest that extracellular AP4A may play a physiological role in the control of insulin and glucagon secretion.
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PMID:Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas. 1051 64

Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative, belongs to a new class of antidiabetic agents structurally related to meglitinide (previously known as the non-sulphonylurea moiety of glibenclamide). Repaglinide and glibenclamide exert reciprocal competitive effects on their respective binding to insulinoma cells. Repaglinide does not affect the metabolism of D-glucose or endogenous nutrients or the biosynthesis of peptides in isolated rat pancreatic islets. Repeated intragastric administration of repaglinide to normal rats increases basal and glucose-stimulated peptide biosynthesis in isolated islets. The major primary action of repaglinide in islets is the closure of ATP-sensitive K+ channels. This agent decreases 86Rb outflow from prelabelled islets perifused in the absence of any exogenous nutrient and protects beta-cells against the inhibitory action of a diazoxide analogue on glucose-stimulated insulin release. The decrease in K+ conductance coincides with stimulation of Ca2+ influx into the islet cells. Meglitinide and its analogues stimulate insulin release more efficiently in the presence of D-glucose or other nutrient secretagogues than in their absence. They are efficient insulinotropic agents in animal models of Type 2 diabetes or in animals infused for 48 h with a hypertonic solution of D-glucose. Repaglinide augments somatostatin secretion, without affecting glucagon release, in isolated perfused rat pancreases exposed to D-glucose. The insulinotropic action of repaglinide was documented in vivo after intravenous or oral administration in normal or Goto-Kakizaki rats. These preclinical investigations suggest that these new insulin secretagogues are well suited as potential insulinotropic tools in the treatment of Type 2 diabetes.
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PMID:Mechanism of action of a new class of insulin secretagogues. 1052 40

In the dt(sz) mutant hamster with idiopathic generalized dystonia, functional abnormalities of several neurotransmitters have been suggested to play a role in the development of symptoms. In the present study, we have used histochemistry with (35)S-ATP labeled oligonucleotides to determine whether these abnormalities are associated with modulation in the expression of neurotransmitter genes in motor regions. We examined the expression of genes encoding cholecystokinin (CCK), somatostatin (SRIF), thyrotropin-releasing hormone (TRH), glutamic acid decarboxylase (GAD), tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) in the cortex and basal ganglia of dystonic hamsters and of non-dystonic control hamsters of a related inbred line and of a non-related outbred line. The distribution of these mRNAs in normal hamster brain was similar to that in normal rat brain. In all cortical regions studied (frontal, parietal and piriformis), the expression of CCK was similar in dystonic and inbred controls but was significantly greater than in outbred controls. In the anterior thalamus, CCK expression was lower in dystonic hamsters than in both control groups. SRIF expression was significantly decreased in the cortex and striatum of dystonic animals than in inbred and outbred control hamsters. GAD expression was lower in the striatum and substantia nigra, pars reticulata of dystonic than in outbred hamsters, but similar values were found in all groups in the other regions studied. TH was lower in the substantia nigra of dystonic than in inbred controls. No changes were found in GAP43 expression. This study demonstrates that changes in modulation of the expression of some peptides and neurotransmitter enzymes can be found in the dystonic hamster, which is in contrast to other animal models such as the dystonic rat, where no such changes have been found. The present data are consistent with previous findings in dt(sz) hamsters that suggest a dysfunction within the basal ganglia-thalamocortical circuits.
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PMID:Expression of cholecystokinin, somatostatin, thyrotropin-releasing hormone, glutamic acid decarboxylase and tyrosine hydroxylase genes in the central nervous motor systems of the genetically dystonic hamster. 1055 May 8

Ca2+ signaling was studied in pancreatic polypeptide (PP)-secreting cells isolated from mouse islets of Langerhans. After measuring the cytoplasmic Ca2+ concentration ([Ca2+]i), the cells were identified by immunocytochemistry. Most PP-cells reacted to carbachol and epinephrine with prompt and reversible elevation of [Ca2+]i, often manifested as slow oscillations. The carbachol effect was muscarinic, because it was inhibited by atropine. Beta-adrenergic elevation of cAMP explains the epinephrine stimulation, which was mimicked by an activator of adenylate cyclase and blocked by an inhibitor of protein kinase A. The responses to carbachol and epinephrine apparently involve depolarization with opening of voltage-dependent Ca2+ channels, because the effects were prevented by the Ca2+ channel antagonist methoxyverapamil and by diazoxide, which activates ATP-dependent K+ (K(ATP)) channels. Being equipped with K(ATP) channels, the PP-cells often responded to tolbutamide or high concentrations of glucose with elevation of [Ca2+]i. Somatostatin reversed the [Ca2+]i elevation obtained by carbachol, epinephrine, tolbutamide, and glucose. These preliminary studies support the idea that glucose has a direct stimulatory effect on the PP-cells, which can be masked by locally released somatostatin. Expressing both K(ATP) channels and voltage-dependent Ca2+ channels, the PP-cells share fundamental regulatory mechanisms with other types of islet cells.
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PMID:Ca2+ signaling in mouse pancreatic polypeptide cells. 1057 15


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