Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyroglutamyl peptidase II (EC 3.4.19.-), a membrane-bound metalloproteinase, is a highly specific TRH-degrading enzyme. Exposure of Y-79 human retinoblastoma cells to 12-0-tetradecanoyl phorbol 13-acetate (TPA) decreased the activity of this enzyme in a time- and concentration-dependent manner (IC50 5 x 10(-9) M). After 15 min of TPA treatment, only 10% of pyroglutamyl peptidase II activity remained. TPA treatment did not affect the activity of the cytosolic enzyme pyroglutamyl peptidase I (EC 3.4.19.3) or the membrane-bound enzyme dipeptidyl peptidase IV (EC 3.4.19.3). Pretreatment of the cells with the protein kinase C inhibitors H-7 or sphingosine prevented the inactivation of pyroglutamyl peptidase II by TPA. The time course of the TPA-mediated effect paralleled the time course of translocation and activation of protein kinase C in this cell line. Immunoblot analysis demonstrated that inactivation of pyroglutamyl peptidase II was not due to dissociation or internalization of this enzyme molecule. Incubation of TPA-activated Y-79 cell membranes with gamma-[32P]-ATP followed by immunoprecipitation revealed a time-dependent phosphorylation of a 48 kilodalton subunit of pyroglutamyl peptidase II. These studies indicate that the phorbol ester effect is mediated by protein kinase C, and reveal a mechanism of potentiation of the action of TRH at its target sites.
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PMID:Rapid inactivation and phosphorylation of pyroglutamyl peptidase II in Y-79 human retinoblastoma cells after exposure to phorbol ester. 197 29

Pyroglutamyl peptidase II (PPII) is a thyrotropin-releasing hormone (TRH) hydrolyzing ectoenzyme with a narrow specificity. In the adenohypophysis, it is present on lactotropes. This study was undertaken in order to determine whether TRH itself regulates PPII activity in the adenohypophysis. After 5 days in culture, dispersed cells from female pituitaries expressed detectable levels of PPII activity when 10(-8) M 3,3',5'-triiodo-L-thyronine was present throughout the culture. 10(-6) M TRH decreased PPII activity with a maximal effect (down to 46% of initial values) at 16 h and an ED50 of 10(-9) M. [3Me-His2]TRH, a potent agonist of the TRH receptor was effective at lower concentrations (ED50: 1.6 x 10(-10) M). Phorbol-12-myristate-13-acetate (PMA; 10(-6) M), a protein kinase C (PKC) activator, diminished PPII activity to 61% or initial values with an ED50 of 2.2 x 10(-8) M. Maximal effects of PMA and TRH were not additive. Neither PMA nor TRH effects were reversed by inhibitors of protein kinases (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine or sphingosine or staurosporine); TRH-induced downregulation of the enzyme was not modified by PMA pretreatment. TRH had no effect on two other ectopeptidases, endopeptidase 24.11 and dipeptidyl aminopeptidase IV. These data demonstrate that TRH specifically downregulates PPII activity in adenohypophyseal cells through TRH receptor activation and suggest that the activation of a presumably calcium-independent PKC mimics the TRH effect. TRH regulation of PPII activity may contribute to adjust lactotrope responsiveness to TRH.
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PMID:Thyrotropin-releasing hormone downregulates pyroglutamyl peptidase II activity in adenohypophyseal cells. 796 91

It is well documented that the release of insulin from isolated perifused islets attenuates over time, despite a continued glucose stimulation. In the current study we have shown that potentiation of insulin release by the intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) is also attenuated after its continuous application. In less than 20 h of maintained stimulus with either hyperglycaemia (11.0 mM glucose) or GIP (10 nM) under hyperglycaemic conditions, insulin release returned to basal values. This was not due to loss of islet viability or reduction in the releasable pool of insulin granules, as 1 mM isobutylmethylxanthine was able to stimulate equivalent insulin release under both conditions. Further examination of chronic GIP desensitization was examined in cultured mouse insulinoma (betaTC-3) cells. GIP-stimulated cAMP production was not greatly affected by the prevailing glucose conditions, suggesting that the glucose dependence of GIP-stimulated insulin release occurs distally to the increase in intracellular cAMP in betaTC-3 cells. The GIP-stimulated cAMP response curve after desensitization was of similar magnitude at all glucose concentrations, but GIP pretreatment did not affect forskolin-stimulated cAMP production. Desensitization of the cAMP response in betaTC-3 cells was shown not to involve induction of dipeptidyl peptidase IV or pertussis toxin-sensitive G-proteins, activation of protein kinase C or protein kinase A, or modulation of phosphodiesterase activity. Homologous desensitization of the insulin-potentiating activity of GIP was found to affect both GIP-stimulated and forskolin-stimulated insulin release, indicating desensitization of distal steps in the stimulus-exocytosis cascade.
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PMID:Role of glucose in chronic desensitization of isolated rat islets and mouse insulinoma (betaTC-3) cells to glucose-dependent insulinotropic polypeptide. 1081 Feb 92

In the next 10 years, major changes in the pharmacotherapy of diabetes can be expected. Both the currently used groups of drugs classified as dipeptidyl-peptidase IV blockers (gliptins) and so-called incretin mimetics (including both natural substances and incretin analogues) will be significantly expanded by up to ten new drugs. In addition, other completely new groups of drugs that act, for instance, via the hepatal mechanism or by influencing the metabolism of steroids will appear. Blocking the absorption of glucose in renal tubules by gliflozines seems to be very promising. In the treatment of diabetes complications, the inhibition of protein kinase C will probably mostly be applied. So-called insulinotropic peptides will very likely be applied by injection and substances reducing insulin resistance as well as new types of substances influencing PPAR nuclear receptors will be administered. In diabetology, antibodies against receptors will be used, too. However, modern pharmacotherapy will undoubtedly come up against the principles of so-called metabolic surgery and other successful technological procedures.
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PMID:[Potential new antidiabetics for the next decade]. 1944 64

Previous studies show that neuropeptide Y(1-36) (NPY(1-36)) and peptide YY(1-36) (PYY(1-36)), by engaging Y1 receptors, stimulate proliferation of spontaneous hypertensive rat (SHR) preglomerular vascular smooth muscle cells (PGVSMCs). In contrast, these peptides have little effect on proliferation of Wistar-Kyoto (WKY) PGVSMCs. Why SHR and WKY PGVSMCs differ in this regard is unknown. Because receptor for activated C kinase 1 (RACK1) can modulate cell proliferation, we tested the hypothesis that differences in RACK1 levels/localization may explain the differential response of SHR vs. WKY PGVSMCs to NPY(1-36) and PYY(1-36). Western blotting for RACK1 in subcellular fractions of cultured SHR and WKY PGVSMCs demonstrated increased levels of RACK1 in the membrane and cytoskeletal subcellular fractions of SHR vs. WKY PGVSMCs. NPY(1-36) and PYY(1-36) stimulated proliferation of SHR PGVSMCs, and siRNA knockdown of RACK1 abrogated this effect. Neither NPY(1-36) nor PYY(1-36) stimulated the proliferation of WKY PGVSMCs. However, in WKY PGVSMCs treated with a RACK1 plasmid, both NPY(1-36) and PYY(1-36) stimulated proliferation. In SHR PGVSMCs, inhibitors of the G(i)/phospholipase C/PKC pathway (a pathway known to be organized by RACK1) attenuated the ability of NPY(1-36) to stimulate the proliferation of SHR PGVSMCs. Our results suggest that RACK1 modulates the ability of PGVSMCs to respond to the proliferative actions of NPY(1-36) and PYY(1-36)and differences in RACK1 levels/localization account for, in part, differential proliferative responses to NPY(1-36) and PYY(1-36) in SHR vs. WKY PGVSMCs. Because dipeptidyl peptidase IV inhibitors increase NPY(1-36) and PYY(1-36) levels, our findings have implications for the use of such drugs in diabetic patients.
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PMID:Role of RACK1 in the differential proliferative effects of neuropeptide Y(1-36) and peptide YY(1-36) in SHR vs. WKY preglomerular vascular smooth muscle cells. 2330 11

Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine L-cells. Enhancing GLP-1 action is an important target for prevention and treatment of type 2 diabetes. Several approaches (GLP-1 analogs, dipeptidyl peptidase IV inhibitors) are being used to develop therapeutic agents using GLP-1 action for the treatment of diabetes. However, an alternative approach is to increase endogenous GLP-1 secretion through modulation of the secretory mechanism in intestinal L cells by pharmaceutical agents or dietary ingredients. In the present study, we demonstrate that curcumin, a yellow pigment isolated from the rhizomes of Curcuma longa L, significantly increases GLP-1 secretion in GLUTag cells, and we clarified the structure-activity relationship using curcumin derivatives. Also, concerning the secretory mechanism, the significant increase in GLP-1 secretion by curcumin involved the Ca(2+)-Ca(2+)/calmodulin-dependent kinase II pathway, and was independent of extracellular signal-regulated kinase, PKC, and the cAMP/PKA-related pathway. These findings provide a molecular mechanism for GLP-1 secretion mediated by foods or drugs, and demonstrate a novel biological function of curcumin in regards to GLP-1 secretion.
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PMID:Curcumin stimulates glucagon-like peptide-1 secretion in GLUTag cells via Ca2+/calmodulin-dependent kinase II activation. 2366 Jan 91