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)

Accumulating data obtained from various animal species indicate that vasopressin (AVP) participates in the regulation of adrenocortical function. AVP doubled aldosterone and cortisol secretion but did not affect corticosterone secretion. Pharmacological studies indicate that the AVP receptors in the cortex belong to the V1 a subtype. Activation of V1 a receptors induces breakdown of membrane phosphoinositides, with subsequent accumulation of inositol phosphates and diacylglycerol. These effects occur after receptor binding, G-protein activation and coupling to a specific phospholipase C. Inositol trisphosphate, transiently produced, induces a rapid release of Ca2+ from intracellular stores. Diacylglycerol activates protein kinase C, which, together with calcium, is responsible for steroid secretion. The early events of AVP action are mediated by two types of G-proteins. One is coupled to phospholipase C, and insensitive to pertussis toxin (probably Gq/11) and a second one, which is inactivated by pertussis toxin (Gi protein), is involved in the stimulation of calcium influx. This Ca2+ influx pathway is very important, as no steroidogenic effect of AVP could be observed when experiments were performed in a calcium-free medium or in pertussis toxin-treated cells. Besides the pituitary, the adrenal is also a source for AVP production. Indeed, AVP is synthesized and secreted by chromaffin cells either present in the medulla or scattered throughout the cortex with a more prominent concentration in zona glomerulosa. AVP receptors are also present on chromaffin cells. However, in contrast to AVP receptors in the cortex, these mainly belong to the V1 b subtype, although V1 a receptors are also detected. The results summarized in this review conclusively indicate that AVP is one of the regulators of both cortex and medulla, an influence which may be mediated in part via pituitary AVP and in part via local production of AVP.
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PMID:Regulation of adrenocortical function by vasopressin. 969 64

The early events of activation were studied in paucibacillary (TT/BT) and multibacillary (BL/LL) leprosy patients by stimulation of their lymphocytes with mitogenic agents (calcium ionophore A23187/PMA) and Micobacterium leprae antigen (PGL-1). Maximum proliferation in response to PMA/A23187 and PGL-1 was observed in the BT/TT patients and the control group, respectively. Inositol triphosphate (IP3) and calcium were constitutively elevated in BT/TT and LL/BL patients. PMA/A23187 caused an increase in both IP3 and [Ca2+]i in BT/TT patients and controls. PGL-1 marginally increased IP3 levels in BT/TT patients. In the LL/BL patients, although PMA/A23187 increased IP3 levels, but no change was seen in [Ca2+]i, PGL-1 had no effect. Protein kinase C levels were seen to be associated with particulate fractions in BT/TT patients and were found to increase further in response to PMA/A23187. PGL-1 did not increase translocation of protein kinase C in controls or LL/BL patients. A preactivated and sensitised state of T-lymphocytes was observed in BT/TT patients, responsive to antigen and mitogens, whereas the cells of LL/BL patients were unresponsive to PGL-1. The altered signal transduction events characterised in the MB patients thus correlate well with the anergic state of their cells.
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PMID:Immunological defect in leprosy patients: altered T-lymphocyte signals. 1022 95

myo-Inositol is a ubiquitous intracellular organic osmolyte and phosphoinositide precursor maintained at millimolar intracellular concentrations through the action of membrane-associated Na+-myo-inositol cotransporters (SMIT). Functional cloning and expression of a canine SMIT cDNA, which conferred SMIT activity in Xenopus oocytes, predicted a 718-amino acid peptide homologous to the Na+-glucose cotransporter with a potential protein kinase A phosphorylation site and multiple protein kinase C phosphorylation sites. A consistent approximately 1.0- to 13.5-kb array of transcripts hybridizing with this cDNA are osmotically induced in a variety of mammalian cells and species, yet SMIT activity appears to vary among different tissues and species. An open reading frame on human chromosome 21 (SLC5A3) homologous to that of the canine cDNA (96.5%) is thought to comprise an intronless human SMIT gene. Recently, this laboratory ascribed multiply sized, osmotically induced SMIT transcripts in human retinal pigment epithelial cells to the alternate utilization of several 3'-untranslated SMIT exons. This article describes an alternate splice donor site within the coding region that extends the open reading frame into the otherwise untranslated 3' exons, potentially generating novel SMIT isoforms. In these isoforms, the last putative transmembrane domain is replaced with intracellular carboxy termini containing a novel potential protein kinase A phosphorylation site and multiple protein kinase C phosphorylation sites, and this could explain the heterogeneity in the regulation and structure of the SMIT.
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PMID:Alternate splicing in human Na+-MI cotransporter gene yields differentially regulated transport isoforms. 1036 95

The purpose of this review is to update the information concerning the intracellular effect of GnRH. Binding of GnRH to a G-protein coupled receptor leads to stimulation of Gq and/or G11 protein and to activation of phospholipase C beta. Inositol 1-4-5-triphosphate and early diacylylycerol are the second messengers required for conventional protein kinase C activation. Activation of phospholipase A2 and phospholipase D are also involved, as demonstrated by the liberation of Arachidonic Acid and Phosphatidic Acid. Pituitary cells also express atypical protein kinase C isoforms which mode of activation is not known. Hypothesis concerning transcriptional regulation are presented.
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PMID:Mechanism of GnRH receptor signaling: from the membrane to the nucleus. 1045 77

Inositol hexakisphosphate (InsP6) inhibits serine/threonine protein phosphatases type-1 (PP1), type-2A (PP2A) and type-3 (PP3) in a concentration-dependent manner. Since the activity of voltage-gated L-type Ca(2+)-channels is increased by inhibition of serine/threonine protein phosphatases, this may explain trhe increased Ca(2+)-channel activity obtained in the presence of InsP6. In insulin-secreting cells, InsP6 is therefore likely to be one of the key elements modulating Ca(2+)-influx over the plasma membrane. InsP6 can also modulate insulin exocytosis in permeabilized cells. Concentrations of InsP6 above 20 microM stimulated insulin secretion at basal Ca(2+)-concentration (30 nM) and primed Ca(2+)-induced exocytosis (10 microM), both effects being due to activation of PKC. Hence, InsP6 can play an important modulatory role in the regulation of insulin exocytosis and the specific role may then be to recruit secretory granules to the site of exocytosis. The fact that some InsP6 is localised to membranes, so being topographically disposed to regulate ion channels as well as exocytosis, and that it has a rapid rate of turnover in glucose-stimulated insulin-secreting cells, suggest novel functions for InsP6 in the insulin secretory process.
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PMID:Inositol hexakisphosphate and beta-cell stimulus-secretion coupling. 1062 50

We studied the role of gastrin in regulating cholangiocyte proliferation induced by bile duct ligation (BDL). In purified cholangiocytes, we evaluated (1) for the presence of cholecystokinin-B (CCK-B)/gastrin receptors, (2) the effect of gastrin on D-myo-Inositol 1,4,5-triphosphate (IP(3)) levels, and (3) the effect of gastrin on DNA synthesis and adenosine 3', 5'-monophosphate (cAMP) levels in the absence or presence of CCK-A (L-364,718) and CCK-B/gastrin (L-365,260) receptor inhibitors, 1, 2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis(acetxymethyl ester) (BAPTA/AM; an intracellular Ca(2+) chelator), and 2 protein kinase C (PKC) inhibitors, 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7) and staurosporin. To evaluate if gastrin effects on cholangiocyte proliferation are mediated by the isoform PKCalpha, we evaluated (1) for the presence of PKCalpha in cholangiocytes and (2) the effect of gastrin on the PKCalpha protein expression in a triton-soluble (containing cytoplasm + membrane) and a triton-insoluble (containing cytoskeleton) fraction. To evaluate the effects of gastrin in vivo, immediately following BDL, gastrin or bovine serum albumin (BSA) was infused by minipumps for 7 days to rats and we measured cholangiocyte growth and cAMP levels. We found CCK-B/gastrin receptors on cholangiocytes. Gastrin increased IP(3) levels. Gastrin inhibited DNA synthesis and cAMP synthesis in cholangiocytes. Gastrin effects on cholangiocyte functions were blocked by L-365,260, BAPTA/AM, H7, and staurosporin but not by L-364,718. Gastrin induced translocation of PKCalpha from cholangiocyte cytoskeleton to membrane. In vivo, gastrin decreased cholangiocyte growth and cAMP synthesis compared with controls. We concluded that gastrin inhibits cholangiocyte growth in BDL rats by interacting with CCK-B/gastrin receptors through a signal transduction pathway involving IP(3), Ca(2+), and PKCalpha.
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PMID:Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/Gastrin receptors via D-myo-inositol 1,4,5-triphosphate-, Ca(2+)-, and protein kinase C alpha-dependent mechanisms. 1086 84

Conjunctival goblet cells secrete mucus in response to cholinergic (muscarinic) agonists, but the underlying signaling pathways activated in this tissue are not well understood. Cholinergic agonists usually activate phospholipase C to produce inositol 1,4,5 trisphosphate and diacylglycerol. Inositol 1,4,5 trisphosphate increases the intracellular Ca(2+)concentration ([Ca2(+)](i)) while diacylglycerol activates protein kinase C (PKC). PKC and Ca(2+), either by itself or with calmodulin, activate cellular functions. Goblet cell glycoprotein secretion, our index of mucin secretion, was measured from pieces of rat conjunctiva with an enzyme-linked lectin assay using the lectin Ulex europaeus agglutinin I (UEA-I). UEA-I selectively recognizes high molecular weight glycoproteins secreted by the goblet cells. Increasing the [Ca(+)](i)with the Ca(2+)ionophore ionomycin stimulated glycoprotein secretion from conjunctival goblet cells. Cholinergic agonist-induced secretion was completely blocked by chelation of extracellular Ca(2+)and by the Ca(2+)/calmodulin-dependent protein kinase inhibitors KN93 and W7 as well as their inactive analogs KN92 and W5. Activation of classical and novel PKC isozymes by phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate stimulated goblet cell glycoprotein secretion. When ionomycin and PMA were added simultaneously, secretion was additive. PKC isozymes were identified by Western blotting analyses with antibodies specific to nine of the 11 PKC isozymes (PKCgamma and zeta were not tested). All nine PKC isozymes were identified in the conjunctival epithelium. The cellular location of the PKC isozymes was determined by immunofluorescence microscopy. Goblet cells contained the classical PKC isozymes PKCalpha, -betaI and -betaII, the novel PKC isozymes PKCepsilon, -theta;, and - mu, and the atypical PKC isozyme PKCzeta. We were unable to determine if PKC activation is required for cholinergic-agonist induced secretion because the PKC inhibitors chelerythrine and staurosporine alone greatly increased secretion. We conclude that Ca(2+)plays a major role in cholinergic agonist-induced conjunctival goblet cell secretion, but this agonist appears not to use Ca(2+)/calmodulin-dependent protein kinases. We also conclude that activated PKC can stimulate goblet cell secretion and that seven different PKC isoforms are present in the goblet cells.
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PMID:Regulation of conjunctival goblet cell secretion by Ca(2+)and protein kinase C. 1109 14

We have previously shown that, in circular muscle cells of the lower esophageal sphincter (LES) isolated by enzymatic digestion, contraction in response to maximally effective doses of acetylcholine (ACh) or Inositol Triphosphate (IP3) depends on the release of Ca2+ from intracellular stores and activation of a Ca2+-calmodulin (CaM)-dependent pathway. On the contrary, maintenance of LES tone, and response to low doses of ACh or IP3 depend on a protein kinase C (PKC) mediated pathway. In the present investigation, we have examined requirements for Ca2+ regulation of the interaction between CaM- and PKC-dependent pathways in LES contraction. Thapsigargin (TG) treatment for 30 min dose dependently reduced ACh-induced contraction of permeable LES cells in free Ca2+ medium. ACh-induced contraction following the low level of reduction of Ca2+ stores by a low dose of TG (10(-9) M) was blocked by the CaM antagonist, CGS9343B but not by the PKC antagonists chelerythrine or H7, indicating that the contraction is CaM-dependent. After maximal reduction in intracellular Ca2+ from Ca2+ stores by TG (10(-6) M), ACh-induced contraction was blocked by chelerythrine or H7, but not by CGS9343B, indicating that it is PKC-dependent. In normal Ca2+ medium, the contraction by ACh after TG (10(-9) M) treatment was also CaM-dependent, whereas the contraction by ACh after TG (10(-9) M) treatment was PKC-dependent. We examined whether PKC activation was inhibited by activated CaM. CGS 9343B inhibited the CaM-induced contraction, but did not inhibit the DAG-induced contraction. CaM inhibited the DAG-induced contraction in the presence of CGS 9343B. This inhibition by CaM was Ca2+ dependent. These data are consistent with the view that the switch from a PKC-dependent pathway to a CaM dependent pathway can occur and can be regulated by cytosolic Ca2+ in the LES.
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PMID:Interaction of calmodulin- and PKC-dependent contractile pathways in cat lower esophageal sphincter (LES). 1179 33

Membrane homeostasis is maintained by exocytosis and endocytosis. The molecular mechanisms regulating the interplay between these two processes are not clear. Inositol hexakisphosphate (InsP(6)) is under metabolic control and serves as a signal in the pancreatic beta cell stimulus-secretion coupling by increasing Ca(2+)-channel activity and insulin exocytosis. We now show that InsP(6) also promotes dynamin I-mediated endocytosis in the pancreatic beta cell. This effect of InsP(6) depends on calcineurin-induced dephosphorylation and is accounted for by both activation of protein kinase C and inhibition of the phosphoinositide phosphatase synaptojanin and thereby formation of phosphatidylinositol 4,5-bisphosphate. In regulating both exocytosis and endocytosis, InsP(6) thus may have an essential integral role in membrane trafficking.
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PMID:Inositol hexakisphosphate promotes dynamin I- mediated endocytosis. 1201 38

Syndecan-4 is a transmembrane heparan sulfate proteoglycan that can regulate cell-matrix interactions and is enriched in focal adhesions. Its cytoplasmic domain contains a central region unlike that of any other vertebrate or invertebrate syndecan core protein with a cationic motif that binds inositol phospholipids. In turn, lipid binding stabilizes the syndecan in oligomeric form, with subsequent binding and activation of protein kinase C. The specificity of phospholipid binding and its potential regulation are investigated here. Highest affinity of the syndecan-4 cytoplasmic domain was seen with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5P)(2)) and phosphatidylinositol 4-phosphate, and both promoted syndecan-4 oligomerization. Affinity was much reduced for 3-phosphorylated inositides while no binding of diacylglycerol was detected. Syndecan-2 cytoplasmic domain had negligible affinity for any lipid examined. Inositol hexakisphosphate, but not inositol tetrakisphosphate, also had high affinity for the syndecan-4 cytoplasmic domain and could compete effectively with PtdIns(4,5)P(2). Since inositol hexaphosphate binding to syndecan-4 does not promote oligomer formation, it is a potential down-regulator of syndecan-4 signaling. Similarly, phosphorylation of serine 183 in syndecan-4 cytoplasmic domain reduced PtdIns(4,5)P(2) binding affinity by over 100-fold, although interaction could still be detected by nuclear magnetic resonance spectroscopy. Only protein kinase Calpha was up-regulated in activity by the combination of syndecan-4 and PtdIns(4,5)P(2), with all other isoforms tested showing minimal response. This is consistent with the codistribution of syndecan-4 with the alpha isoform of protein kinase C in focal adhesions.
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PMID:Regulation of inositol phospholipid binding and signaling through syndecan-4. 1237 72


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