Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of Ca2+ and calmodulin on phosphorylation of islet secretory granule proteins was studied. Secretory granules were incubated in a phosphorylation reaction mixture containing [32P]ATP and test reagents. The 32P-labeled proteins were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the 32P content was visualized by autoradiography, and the relative intensities of specific bands were quantitated. When the reaction mixture contained EGTA and no added Ca2+, 32P was incorporated into two proteins with molecular weights of 45,000 and 13,000. When 10(-4) M Ca2+ was added without EGTA, two additional proteins (58,000 and 48,000 Mr) were phosphorylated, and the 13,000-Mr protein was absent. The addition of 2.4 microM calmodulin markedly enhanced the phosphorylation of the 58,000- and 48,000-Mr proteins and resulted in the phosphorylation of a major protein whose molecular weight (64,000 Mr) is identical to that of one of the calmodulin binding proteins located on the granule surface. Calmodulin had no effect on phosphorylation in the absence of Ca2+ but was effective in the presence of calcium between 10 nM and 50 microM. Trifluoperazine and calmidazolium, calmodulin antagonists, produced a dose-dependent inhibition of the calmodulin effect. 12-O-tetradecanoylphorbol 13-acetate, a phorbol ester that activates protein kinase C, produced no increase in phosphorylation, and 1-(5-isoquinoline sulfonyl)-2-methyl piperazine dihydrochloride, an inhibitor of protein kinase C, had no effect. These results indicate that Ca(2+)-calmodulin-dependent protein kinases and endogenous substrates are present in islet secretory granules.
Diabetes 1991 Aug
PMID:Ca(2+)-calmodulin-dependent phosphorylation of islet secretory granule proteins. 190 48

Contractile responses to calcium were examined in the K+-depolarized duodenum from normal and alloxan-diabetic rats. In addition, verapamil and trifluoperazine which are well-known calcium channel blocker and calmodulin inhibitor respectively were used as tools in order to approach to the mechanism of changes resulting from diabetes. Decreased contractile responses to calcium were observed in the alloxan diabetic rat duodenum compared to normals. Trifluoperazine-induced non-competitive inhibition was significantly affected depending on diabetes, while verapamil-induced competitive inhibition was not changed. The non-competitive inhibition affinity constant for trifluoperazine was significantly elevated in the K+-depolarized duodenum from alloxan-diabetic rats. On the basis of findings obtained in this study, possible mechanism of the effect of experimental diabetes on the calcium-induced contraction is discussed.
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PMID:Altered responses to calcium and trifluoperazine in K+-depolarized duodenum from alloxan diabetic rats. 343 25

It may now be possible to identify certain intracellular events that impact specifically on secretion-granule fusion to the plasma membrane or on granule lysis. Secretion vesicles in isolated rat islets appear to translocate somatostatin (SRIF) receptors from the Golgi apparatus to the plasma membrane. We have proposed that secretion granule fusion to the plasma membrane can be determined by measuring recruitment of SRIF receptors to the surface membrane. Granule lysis can be assessed by measuring insulin release. To activate cyclic AMP (cAMP)-dependent pathways, we employed isobutylmethylxanthine (IBMX, 400 microM), glucagon (10 microM), and forskolin (20 microM), a diterpene activator of adenylate cyclase. These agents evoked rapid release of insulin (from 0.41 +/- 0.02 to 1.88 +/- 0.02; 0.41 +/- 0.02 to 1.93 +/- 0.08; and 0.41 +/- 0.02 to 1.66 +/- 0.03 microU/islet/min, respectively, P less than 0.001). There was no concomitant recruitment of SRIF receptors. Somatostatin (10 micrograms/ml), which inhibits cAMP-stimulated protein phosphorylation, suppresses insulin release evoked by IBMX, glucagon, or forskolin (inhibition: 80, 75, or 82%, respectively). In contrast, trifluoperazine (10 microM), an inhibitor of calmodulin, did not suppress insulin release induced through cAMP-dependent pathways. Trifluoperazine suppresses glucose-induced insulin release and the recruitment of SRIF receptors to the surface membrane, suggesting the possible role of calmodulin in promoting secretion-granule fusion with the plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 Apr
PMID:Calmodulin and cyclic AMP. Possible different sites of action of these two regulatory agents in exocytotic hormone release. 620 Mar 77

The effects of Ca2+-calmodulin on adenylate cyclase activity in EGTA-washed, 27000 g particulate fractions of mouse and rat pancreatic islets were studied. Ca2+ (10 microM)-calmodulin (1 microM) stimulated adenylate cyclase activity 53.1 +/- 5.2 (N = 6)% in the particulate fraction of rat islets. Trifluoperazine (50 microM), a specific inhibitor of calmodulin, inhibited the Ca2+-calmodulin activation of the adenylate cyclase activity of this fraction of rat islets. These results confirm previous reports dealing with Ca2+-Calmodulin and rat islet adenylate cyclase [Valverde, Vandermeers. Anjaneyulu & Malaisse (1979) Science 206, 225-227; Sharp, Wiedenkeller, Kaelin, Siegel & Wollheim (1980) Diabetes 29, 74-77]. In contrast, however, Ca2+ (1-100 microM)-calmodulin (1-10 microM) did not stimulate the adenylate cyclase activity in the EGTA-washed particulate fraction of mouse islets, and trifluoperazine (50 microM) did not inhibit the adenylate cyclase activity of this fraction of mouse islets, although some remaining calmodulin [0.18 +/- 0.05 (n = 3) microgram/mg of protein] could be demonstrated. GTP (10 microM) enhanced islet adenylate cyclase activity considerably, but did not confer any sensitivity towards Ca2+-calmodulin on mouse islet adenylate cyclase. The results question the role of calmodulin in the Ca2+-dependent rise in cyclic AMP evoked by glucose in pancreatic islets.
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PMID:Differential effects of Ca2+-calmodulin on adenylate cyclase activity cyclase activity in mouse and rat pancreatic islets. 675 27

Trifluoperazine (TFZ), a phenothiazine drug, penetrates into human erythrocytes and releases oxygen by interaction with hemoglobin. TFZ-induced oxygen release from hyperglycemic erythrocytes isolated from diabetic patients is considerably less compared to that from the cells of normoglycemic individuals. In diabetes mellitus, hemoglobin is significantly glycated by glucose. Non-glycated hemoglobin, HbA0 and its major glycated analog, HbA1c have been separated from the blood samples of diabetic patients. TFZ releases considerable amount of oxygen from HbA0, but very little from HbA1c. Spectrofluorimetric studies reveal that TFZ forms excited state complexes with both HbA0 and HbAlc. Titration of HbA0 with TFZ in a spectrophotometric study exhibits two isosbestic points. Similar experiment with HbAlc causes gradual loss of the Soret peak without appearance of any isosbestic point indicating a possibility of heme loss during interaction, which is also supported by gel filtration experiment and SDS-PAGE experiment followed by heme staining. The results suggest that drug action on hemoglobin is influenced by glycation-induced structural modification of the protein.
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PMID:Effect of glycation of hemoglobin on its interaction with trifluoperazine. 1675 86

Trifluoperazine is a conventional antipsychotic whose use has been limited with the arrival of relatively new atypical antipsychotics. However, conventional antipsychotics are utilized in the management of psychiatric illnesses comorbid with metabolic disorders such as diabetes or dyslipidemia. Though trifluoperazine has been known to cause extrapyramidal symptoms, rarely ophthalmic symptoms manifest. Here, we discuss the rare occurrence of newly-emergent nystagmus in an individual with persistent hallucinatory disorder and comorbid diabetes mellitus treated with trifluoperazine.
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PMID:An Unusual Occurrence of Trifluoperazine-Induced Nystagmus in Persistent Hallucinatory Disorder-A Case Report. 3314 10