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 concentration of extracellular calcium rightly regulates calcitonin secretion by calcium influx through dihydropyridine-sensitive voltage-dependent calcium channels; the result is an increase in intracellular calcium. There also exists a cAMP-dependent pathway of calcitonin release activated by glucagon or growth hormone releasing hormone. In thyroid C-cells, as in all cells, there is dual regulation of adenylate cyclase, mediated by inhibitory or stimulatory G proteins; glucagon stimulated cAMP production can be inhibited by somatostatin via pertussis toxin sensitive inhibitory G proteins. Somatostatin inhibits not only cAMP dependent but also calcium-dependent calcitonin secretion. Furthermore, somatostatin inhibits voltage dependent calcium channel currents thereby lowering cytosolic calcium. These actions also involve a pertussis toxin-sensitive inhibitory G protein but they occur independently of changes in the cytosolic cAMP concentration. Thus multiple interactions between second messenger systems at different cellular levels modulate calcitonin secretion.
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PMID:Regulation of calcitonin secretion in vitro. 822

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.
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PMID:Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade. 866 50

Depression frequently coexists with dementia, although in many cases the depression is not recognized clinically. Depression represents a major additional burden in dementia, not only for the patients but also for families, caregivers, and, economically, society as a whole. However, depression in patients with dementia does respond to treatment, and appropriate therapy can significantly improve the well-being of these patients. Depression in patients with dementia is currently treated with a variety of standard antidepressive agents (tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), but none is free from significant side effects. Moreover, the use of these drugs is often complicated by a number of age-related factors or effects on the cholinergic neurotransmitter system. Consequently, an antidementia treatment with concomitant antidepressive properties and an acceptable benefit/risk ratio would represent an attractive therapeutic option. The pathogenesis of depression in patients with dementia is not well understood, but may be related to increased intracellular calcium ions in the CNS, the so-called "calcium hypothesis." This hypothesis may explain why some calcium antagonists exert psychotropic effects, including putative antidepressant activity. Animal models and clinical data provide support for the use of calcium channel antagonists for the treatment of depression, with the potential for good tolerability. The latter aspect is especially important for elderly patients with dementia. Although antidepressive effects have been seen with a number of calcium channel antagonists, the dihydropyridine derivative nimodipine shows particular potential for clinical use, perhaps because nimodipine is one of the most lipophilic of these drugs and therefore achieves high concentrations in the CNS, and because of the unique biochemical properties of the dihydropyridine compounds compared with other L type calcium channel blockers. Nimodipine also increases somatostatin levels in CSF, one of the cardinal biochemical deficits in Alzheimer's disease. Data obtained incidentally from the use of nimodipine in the treatment of elderly demented patients clearly demonstrate significant antidepressant activity by the drug in this patient group. Formal clinical evaluation is therefore recommended to establish more clearly the therapeutic benefits offered by nimodipine in patients who suffer from both dementia and depression.
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PMID:The management of coexisting depression in patients with dementia: potential of calcium channel antagonists. 903 70

The modulation of a cloned neuronal calcium channel was studied in a human embryonic kidney cell line (HEK293). The HEK293 cells were stably transfected with the alpha1Ed cDNA, containing the pore forming subunit of a neuronal class E calcium channel. Inward currents of 25 +/- 1.9 pA/pF (n = 79) were measured with the cloned alpha1Ed-subunit. The application of the peptide hormone somatostatin, carbachol, ATP or adenosine reduced the amplitude of Ca2+ and Ba2+ inward currents and exhibited a slowing of inactivation. This inhibitory effect by somatostatin was significantly impaired after pre-incubating the transfected cell line with pertussis toxin (PTX). Internal perfusion of the cells with the G-protein-inactivating agent GDP-beta-S or with the permanently activating agent GTP-gamma-S also attenuated the somatostatin effect. The inhibition indicates that modulation of the alpha1Ed-mediated Ca2+ current involves pertussis toxin-sensitive G-proteins. The block of Ca2+ and Ba2+ inward currents by somatostatin is also found in cells expressing a truncated alpha1Ed-subunit which lacks a 129-bp fragment in the C-terminus. This fragment corresponds to the major structural difference between two native human alpha1E splice variants. As somatostatin inhibits inward currents through both, the cloned alpha1Ed- and the truncated alpha1Ed-DEL-subunit, the hormone-mediated modulation is independent from the presence of the 129-bp insertion in the C-terminus.
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PMID:Receptor-mediated modulation of recombinant neuronal class E calcium channels. 918 73

1. The present study examines the hypothesis of G protein subtype selectivity in receptor-induced inhibition of calcium channel currents (ICa) in the insulin-secreting RINm5F and pituitary GH3 rat cell lines. Specificity of receptor coupling to G proteins was studied by infusion of purified G alpha isoforms into cells via a patch pipette. 2. In RINm5F cells, the neuropeptide galanin inhibited dihydropyridine (DHP)- and omega-conotoxin-sensitive components of ICa and slowed down their activation kinetics. In GH3 cells, DHP-sensitive ICa was inhibited by galanin, as well as by somatostatin and carbachol. Agonist-induced ICa inhibition was suppressed by pertussis toxin (PTX) pretreatment of the cells. In PTX-pretreated cells of either cell line, the response to galanin was restored only by the G alpha o1 subunit. Following PTX treatment of GH3 cells, only the G alpha o1 subunit restored carbachol-induced inhibition of ICa, whereas only the G alpha o2 subunit restored somatostatin-induced inhibition of ICa. G(i) subtypes had no effect on ICa inhibition. 3. Both cell lines expressed two distinct immunoreactive Go proteins. Whereas in RINm5F cell membranes Go1 was found to be the predominant isoform, we detected more Go2 than Go1 in GH3 cell membranes. Nevertheless, all agonists stimulated incorporation of the photoreactive GTP analogue [alpha-32P]GTP azidoanilide into both G(o) isoforms. 4. The results indicate that the same Go subtype, i.e. Go1, mediates galanin-induced inhibition of ICa in both cell lines and that the Go subtype specificity of receptor-G protein coupling is confined to intact cells.
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PMID:Receptors couple to L-type calcium channels via distinct Go proteins in rat neuroendocrine cell lines. 926 13

Previous studies have demonstrated that growth hormone (GH) release in goldfish is under the stimulatory control of gonadotropin-releasing hormone (GnRH) and dopamine and the inhibitory control of somatostatin (SRIF). GnRH stimulation is mediated through protein kinase C (PKC)- and calcium-dependent mechanisms, whereas dopamine D1 receptor activation increases GH secretion through cyclic (c) AMP-dependent intracellular signal transduction pathways. In this study, the mechanisms of SRIF inhibition on GH secretion were examined using primary cultures of dispersed goldfish pituitary cells in static incubation. Application of 1 microM SRIF inhibited the GH-release responses to 100 nM salmon GnRH, 100 nM chicken GnRH-II, and 1 microM SKF38393, a D1 agonist. These results indicate that inhibitory action of SRIF on stimulated GH release is direct, at the level of the pituitary cells. Addition of SRIF reduced the GH release responses to two activators of PKC (100 microM dioctanoyl glycerol and 100 nM tetradecanoyl phorbol acetate) and to two ionophores (10 microM A23187 and 10 microM ionomycin). Similarly, SRIF abolished the GH responses to an activator of adenylate cyclase (10 microM forskolin), a membrane-permeant cAMP analog (1 mM 8-bromo-cAMP), and a voltage-sensitive calcium channel agonist (1 microM Bay K 8644). Taken together, these observations indicate that the inhibitory actions of SRIF on D1- and GnRH-stimulated GH release can be exerted at sites distal to cAMP production and PKC activation, respectively. SRIF also exerts its effect at sites distal to calcium mobilization. Since SRIF inhibition was more effective against Bay K 8644-induced response than against ionophore-induced GH response, an inhibitory action at the level of extracellular calcium entry through voltage-sensitive channels is also possible.
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PMID:Somatostatin inhibition of growth hormone release in goldfish: possible targets of intracellular mechanisms of action. 940 21

In NG108-15 cells inhibition of both N-type calcium channel current and adenylyl cyclase by somatostatin (SRIF) was not sustained but rapidly desensitized in the continued presence of the drug. The degree and rate of desensitization were concentration-dependent, and the desensitization was homologous with respect to the delta-opioid receptor. We have been unable to obtain evidence for the involvement of G protein-coupled receptor kinases (GRKs) in this desensitization. SRIF-induced desensitization of N-type calcium channel currents was not reduced in cells stably overexpressing a dominant negative mutant of GRK2 or following intracellular dialysis with GRK2- and GRK3-blocking peptides or with heparin. Inhibitors of protein kinase A, protein kinase C, and protein kinase G were also without effect. In contrast, both the rate and degree of SRIF-induced desensitization were reduced by pretreatment with phenylarsine oxide or concanavalin A, both inhibitors of receptor endocytosis. Furthermore, SRIF-induced desensitization was enhanced by monensin, which prevents receptor recycling back to the plasma membrane. Similarly, SRIF-induced desensitization of adenylyl cyclase inhibition was not reduced in cells stably overexpressing dominant negative mutant GRK2 but was reduced in cells pretreated with the receptor endocytosis inhibitor hyperosmotic sucrose or concanavalin A. These data are consistent with the view that SRIF-induced desensitization in NG108-15 cells results from receptor internalization.
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PMID:Somatostatin receptor desensitization in NG108-15 cells. A consequence of receptor sequestration. 983 85

The appropriate management of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) still remains controversial. Some patients show a response to treatment with diazoxide or somatostatin, but a number of children require total or near-total pancreatectomy to control hyperinsulinism. Recent studies suggest a dysfunction in the adenosine triphosphate-sensitive potassium channel present in the plasma membrane of pancreatic beta-cells in PHHI. The closure of these channels initiating the depolarization of the beta-cell membrane and opening of calcium channels results in an increase in intracellular calcium which triggers insulin secretion. A calcium channel blocking agent has been shown to block this process and decrease insulin secretion of the nesidioblastotic beta-cells in vitro and to control the hyperinsulinemic hypoglycemia of the patient in vivo. To examine the efficacy of calcium channel blocker therapy, three patients with PHHI were treated with nifedipine. PHHI was diagnosed by inappropriately high insulin levels for low blood glucose levels at 8-10 days of age. Normoglycemia was maintained by a high dose of glucose infusion at a rate of 14-16 mg/kg/min. Therapy using diazoxide and/or somatostatin analogue failed to restore euglycemia in these three patients. The first patient underwent near-total pancreatectomy; however, hyperinsulinism recurred 30 days after surgery. All patients were started on short acting nifedipine at a dose of 0.3 mg/kg/day per os in four doses. To maintain blood glucose levels in normal ranges, the dose of nifedipine was progressively increased to 0.7-0.8 mg/kg/day. Glucose infusion rate to restore euglycemia decreased and was discontinued on the 4th to 10th day of nifedipine treatment. The patients, who have now been followed on nifedipine therapy for over 12 months, are normoglycemic with normal insulin levels. The growth and neuromotor development of the patients are unremarkable except for mild developmental delay of the patient who underwent near-total pancreatectomy. No side effects were encountered at the doses used. In conclusion, calcium channel blocking agents can be used with efficacy and safety in PHHI to control the hyperinsulinemia.
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PMID:Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. 1061 46

The present study investigated the mechanisms mediating the actions of the immunosuppressive drug cyclosporine A (CsA) on human pulmonary artery smooth muscle cell (PASMC) proliferation. The new hydroxyethyl derivative of D-serine(8)-cyclosporine, SDZ IMM 125, was used for comparison. CsA-induced proliferation was determined by incorporation of [(3)H]thymidine ([(3)H]Thy). CsA in the concentration range between 0.1 nM and 0.1 microM induced a concentration-dependent increase in proliferation after 24, 48, and 72 hr of incubation. Higher CsA concentrations were cytotoxic. When proliferation experiments were performed in the presence of a monoclonal antibody against endothelin-1 (ET-1), CsA-induced proliferation was totally inhibited. No inhibition occurred in the presence of the same antibody when heat-inactivated or a non-specific monoclonal antibody. In parallel, CsA increased the production of ET-1, as determined by radioimmunoassay. Incubation of PASMCs with ET-1 at the concentration range at which the latter was released by CsA induced cell proliferation. The somatostatin derivative Sandostatin (SDT; octreotide), which is an inhibitor of the growth of smooth muscle cells as well as a potent inhibitor of ET-1 secretion, inhibited both the CsA-induced ET-1 release and the increase in [3H]Thy incorporation by PASMCs. A similar effect was observed for the calcium channel blocker verapamil (VP). SDZ IMM 125 induced weaker effects than CsA in terms of PASMC proliferation and ET-1 secretion. In conclusion, CsA increased the rate of proliferation of PASMCs, while SDZ IMM 125 induced a weaker effect. Anti-ET-1 antibody, VP, and SDT significantly inhibited CsA-induced PASMC proliferation.
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PMID:Strategies to antagonise the cyclosporine A-induced proliferation of human pulmonary artery smooth muscle cells: anti-endothelin-1 antibodies, verapamil, and octreotide. 1075 56

In the nervous system, signals transmitted across synapses are known to regulate gene expression in the postsynaptic cells. This process often involves membrane depolarization and subsequent elevation of intracellular Ca(2+). We have previously demonstrated in fetal cerebrocortical cells, that somatostatin (SS) mRNA levels can be induced by depolarizing agents such as high potassium concentrations and veratridine (VTD), and that these effects are calcium dependent. SS expression is regulated by cAMP, and in the cerebral cortex adenylate cyclase activity is regulated through fluctuations in intracellular Ca(2+) concentrations. The present experiments were undertaken to determine the mechanism by which calcium upregulates the levels of SS mRNA. Cerebrocortical cells from 17-day-old fetuses were exposed to the different agents for 24 h and the levels of SS mRNA were measured by Northern blot. Incubation of cells with the calcium channel antagonist nifedipine (Nf), the calcium chelating agent EGTA, calcium free KRB and the calcium calmodulin inhibitors trifluoroperazine (TFP) and the napthelene sulfonamide, W7, resulted in the inhibition of K(+)-induced SS mRNA levels. K(+)-evoked depolarization increased the intracellular concentration of cAMP and this effect was antagonized by verapamil (VPM). Forskolin (Fk) provoked a higher increment in cAMP concentration than potassium, although the induction of SS mRNA was more evident following K(+) depolarization indicating a lack of correlation between levels of cAMP and induction of SS mRNA. The role of K(+)-induced cAMP on the increment of SS mRNA that occurred upon membrane depolarization was further explored with the inhibitor of protein kinase A (PKA), Rp cAMP whose presence significantly reduced depolarization-induced SS mRNA levels. This study confirms that Ca(2+) influx is required for K(+)depolarization-induced stimulation of cAMP whereby the increment of SS mRNA is partly produced.
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PMID:Potassium depolarization-induced cAMP stimulates somatostatin mRNA levels in cultured diencephalic neurons. 1085 86


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