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)

Phosphatidylserine (PS) is a necessary cofactor for protein kinase C (PKC) activation, and changes in the synthesis of PS have been shown to participate in the mechanism(s) involved in the transmembrane signaling of interleukin 1 (IL-1). In view of the age-associated defects in T-cell functions, in the present study we have addressed the question of whether an in vivo treatment with PS might interfere with such processes. Furthermore, the effect of an in vitro treatment with PS in human peripheral blood monocytes (PBMC) or splenocytes activated with a lectin mitogen, on the expression of IL-2 receptor, was assessed. While the process of ageing was accompanied by a marked decline of humoral response monitored by anti-BSA antibodies (of the IgG class) production, following immunization with BSA in complete Freund adjuvant, chronic treatment with PS (50 mg/kg, in drinking water), reversed this effect, raising specific antibody titers to levels practically indistinguishable from those measured in young animals. Pharmacological depression of humoral immune response induced by a treatment of adult animals with dexamethasone was similarly reversed by a chronic treatment with PS. While only a pharmacological concentration (10(-5) M) of PS significantly increased IL-2 receptor expression in activated human PBMC, simultaneous treatment of PBMC with inactive doses of PS and the pharmacological activator of PKC (phorbol myristate acetate, PMA, 10(-8) M) resulted in a synergistic stimulation of Tac+ cells. Furthermore, in cultures of rat splenocytes PS (10(-6) M) significantly stimulated the expression of IL-2 receptor, and concomitant addition of PS (10(-7) M) to Con A-stimulated splenocytes produced a significant potentiation of IL-2 receptor induction. The present results indicate that in vivo treatment of ageing animals with the specific phospholipid PS is able to reverse the physiological decline of the humoral immune response induced by the ageing process. Moreover, treatment of young rats with PS reversed the pharmacological associated depression of specific antibody production. The in vitro effects of the phospholipid on human PBMC and rat splenocytes might suggest that PS is implicated in T-cell activation through its action on IL-2 receptor.
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PMID:Phosphatidylserine counteracts physiological and pharmacological suppression of humoral immune response. 239 81

Activation of protein kinase C (PKC) via neurotransmitter coupling processes has been associated with long-term potentiation (LTP) or classical conditioning, but whether natural variation in PKC activity affects learning performance remains to be determined. Inbred strains of mice differ in their ability to exhibit spatial reference memory as measured by the Morris water task. C57BL/6Ibg (C57) mice perform the task better than DBA/2Ibg (DBA) mice, which show relatively little spatial preference. Hippocampal PKC activity extracted from the particulate fraction was lower in DBA mice than in C57 mice. To examine the potential relationship of PKC activity with spatial learning performance, 11 C57BL/6J x DBA/2J recombinant inbred strains (BXD RIs) were trained in the place learning version of the Morris water task. Cortical and hippocampal PKC activities were measured. Variation in spatial learning performance and PKC activity from cortex and hippocampus was observed. A positive significant correlation was observed between measures of spatial learning accuracy and hippocampal PKC in these strains. No correlation was observed between spatial learning accuracy and cortical PKC activity. These data suggest that animals with lower hippocampal PKC activity may have problems performing spatial reference memory tasks with the same degree of accuracy as those with higher hippocampal PKC activity.
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PMID:Hippocampal protein kinase C activity is reduced in poor spatial learners. 240 Sep 4

Sn-1,2-diacylglycerols (DAG) and ionized-free calcium can act as intracellular second messengers for cell activation. Traditionally, T-lymphocyte activation is assessed by measurements of DNA synthesis or lymphokine production, but these responses require several days to occur and involve multiple intermediary regulatory steps. In contrast, we have found that T-lymphocytes demonstrate rapid enhancement of A-(alanine-favoring) system amino acid uptake when treated with DAG or ionomycin. A 30-40% increase in the initial velocity of uptake (vi) of the synthetic A-system specific amino acid, methylamino-isobutyric acid (MeAIB), was measured following 5 min of exposure to DAG or ionomycin. The vi was enhanced 60% from 12 to 19 mumol/liter cell water per min after 30 min exposure of T-cells to optimal concentrations of dioctanoylglycerol (30 microM), oleoylacetylglycerol (30 microM), or ionomycin (5 microM) (P less than .01 for each agent). A 50-fold excess of non-radioactive MeAIB inhibited 80% of [14C]MeAIB uptake in both unstimulated and stimulated cells, indicating that uptake remained largely carrier-mediated on treatment with these agents. Cycloheximide, 100 micrograms/ml, inhibited protein synthesis but did not block the A-system amino acid transport enhancement induced by DAG or ionomycin. The DAG-induced increase in the vi was blocked 40% with 100 microM H-7, an inhibitor of protein kinase C. H-7 treatment did not inhibit the ionomycin-induced A-system enhancement. A marked increase in cytoplasmic free calcium was measured when T-lymphocytes were exposed to ionomycin but not on DAG exposure, and the A-system effect of ionomycin but not DAG was blocked by extracellular EGTA. These data are compatible with two pathways for rapid enhancement of A-system amino acid uptake in T-lymphocytes. DAG stimulation is mediated via protein kinase C whereas ionomycin produces an A-system effect of similar magnitude independent of protein kinase C by an increase in cytoplasmic calcium.
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PMID:Diacylglycerol and calcium induce rapid enhancement of A-system amino acid transport by independent mechanisms in human T-lymphocytes. 250 95

Toad urinary bladder epithelial cells grown in culture (primary) show a significant increase in water-soluble inositol phosphates when treated with 10(-8) M vasopressin (AVP), but not with (1-deamino-8-D-arginine)vasopressin (dDAVP), a V2-agonist. The increase in inositol phosphates was blocked by the V1-antagonist, d(CH2)5Tyr(Me)AVP, suggesting a V1-coupled phosphoinositide breakdown. The V1-antagonist had no effect on basal adenylate cyclase activity nor on that stimulated by AVP. However, the V1-antagonist was found to attenuate the hydrosmotic response of AVP, suggesting some role of the V1-receptor cascade in the water flow response. Mezerein (MZ), a non-phorbol activator of protein kinase C (PKC) increased osmotic water flow when added to the mucosal surface. The response was less in magnitude and occurred over a longer period (90 min) than that observed with AVP. In an attempt to emulate the V1-response, activation of PKC, and an increase in intracellular calcium, toad bladders were incubated with MZ and the calcium ionophore A23187 (IP). It was found that IP enhanced the water flow response to MZ at all times measured. Mz and IP were also found to enhance cAMP-mediated water flow, suggesting that apical membrane permeability may be regulated in part through V1-receptor stimulation and its respective second messengers. Collectively, these observations suggest that the V1 receptor may play a role not only as part of a negative feedback system, but also as an integral component of the enhanced water permeability that occurs at the apical membrane.
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PMID:Contribution of the vasopressin V1 receptor to its hydrosmotic response. 252 41

Proteins in lacrimal gland fluid are secreted primarily by the acinar cells. Secretory proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, stored in secretory granules, and released upon a change in the cellular level of second messenger. The second messenger level is controlled by a process termed signal transduction. Agonists, primarily neurotransmitters in the lacrimal gland, bind to receptors in the basolateral membrane of secretory cells. This interaction activates enzymes in the membrane that cause production of second messengers. It has been hypothesized that second messengers stimulate secretion by activating specific protein kinases to phosphorylate proteins important for secretion. In the lacrimal gland, cholinergic agonists stimulate protein secretion. They act by activating phospholipase C to break down phosphatidylinositol bisphosphate into 1,4,5-inositol trisphosphate (1,4,5-IP3) and diacylglycerol (DAG). 1,4,5-IP3 causes release of Ca2+ from intracellular stores. This Ca2+, perhaps in conjunction with calmodulin, activates specific protein kinases that may be involved in secretion. DAG activates protein kinase C which stimulates protein secretion. alpha 1-Adrenergic agonists also stimulate lacrimal gland protein secretion. These agonists use a pathway that is separate from that utilized by cholinergic agonists and vasoactive intestinal peptide (VIP). The specific pathway has not been identified but may be DAG and protein kinase C. VIP, beta-adrenergic agonists, alpha-melanocyte stimulating hormone, and adrenocorticotropic hormone are lacrimal gland secretagogues. They activate adenylate cyclase to produce cAMP. cAMP stimulates protein kinase A, which perhaps causes protein secretion. Thus, three separate cellular pathways stimulate lacrimal gland protein secretion. Cholinergic agonists and VIP also stimulate lacrimal gland fluid secretion, and the same signal transduction pathways utilized by these agonists to stimulate protein secretion are most likely used for electrolyte and water secretion.
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PMID:Signal transduction and control of lacrimal gland protein secretion: a review. 254 11

Neurohumoral agents modulate intestinal transport by interactions with cell membrane receptors. Intracellular second messenger systems implicated in mediation of membrane receptor regulation of cellular events include the phosphoinositide and adenylate cyclase systems. In this study we have investigated the effects of direct postreceptor activation of key components of these systems on intestinal water and electrolyte transport. Rabbit ileal segments (n = 35) were arterially perfused ex vivo with an oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing 14C-polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- in six experimental groups were calculated for three 20-minute periods: basal, drug infusion, and recovery. The control group had no drug infusion. Two phorbol esters--phorbol 12, 13-diacetate (PDA; 10(-5) mol), and phorbol 12, 13-dibutyrate (PDB; 10(-5) mol)--were used to activate protein kinase C, an important component of the phosphoinositide system. The inactive 4 alpha-phorbol 12, 13-didecanoate (PDD; 10(-5) mol) served as a drug-infused control. Forskolin at two doses (FOR; 10(-5) mol and 10(-6) mol) was used to activate adenylate cyclase. The control and PDD groups had no changes in the flux of water and electrolytes. Both PDA and PDB had proabsorptive effects, with the more lipophilic and potent phorbol ester (PDB) having a more pronounced, significant effect (p less than 0.05). FOR caused significant secretion of H2O, Na+, and Cl- in a dose-dependent fashion (p less than 0.05). These results indicate that direct protein kinase C activation causes a proabsorptive effect and that direct activation of adenylate cyclase causes a secretory effect in the isolated small bowel. The activation status of these second messenger systems has a major influence on the transport state of the intestine.
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PMID:Postreceptor mechanisms of small-bowel water and electrolyte transport. 254 96

Bradykinin inhibits vasopressin-stimulated water transport in cortical collecting tubular cells. The biochemical mechanism of this effect was explored by means of primary cultures of rabbit cortical collecting tubular cells. Bradykinin was found to produce a rapid release of calcium from intracellular stores, an increase in sn-1,2-diacylglycerol levels, and a fivefold increase in membrane-bound protein kinase C activity, consistent with stimulation of phospholipase C and activation of protein kinase C in rabbit cortical collecting tubular cells. In addition, bradykinin produced a dose-dependent 46% inhibition of vasopressin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) formation. Pretreatment with the protein kinase C inhibitors, H-7 and staurosporine, reversed the bradykinin-mediated inhibition of vasopressin-stimulated cAMP accumulation. In contrast, pretreatment with either the phospholipase A2 inhibitor, mepacrine, or pertussis toxin did not prevent the inhibitory effect of bradykinin on vasopressin-stimulated cAMP production, suggesting that the effects are not mediated by prostaglandin E2 or activation of a pertussis-toxin sensitive guanine nucleotide regulatory protein (e.g., Gi). Because bradykinin also inhibits isoproterenol-stimulated cAMP formation but does not inhibit either basal-, forskolin-, or cholera toxin-stimulated cAMP accumulation, the site of this inhibition appears to involve the hormone receptor or coupling of the receptor to the stimulatory guanine nucleotide regulatory subunit (Gs). The results demonstrate that bradykinin stimulates phospholipase C leading to activation of protein kinase C, which then inhibits vasopressin-stimulated cAMP production at the level of the hormone receptor or coupling of the receptor to Gs in cultured cortical collecting tubular cells.
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PMID:Bradykinin activates protein kinase C in cultured cortical collecting tubular cells. 255 39

Previous studies of enzyme secretion from isolated pancreatic acinar cells and of isolated zymogen granules (ZG) have reported that both a Cl- and a K+ permeability are present on the ZG membrane. It has been suggested that ion influx via these permeability pathways, followed by water movement is required for granular swelling which appears to be intimately related to exocytosis. However, little is known about the regulation of these pathways by secretagogues. Evidence suggests that cAMP-protein kinase A and diacylglycerol-protein kinase C are second messengers in stimulation of exocytosis. In the present study we have examined ion permeability pathways in ZG isolated from control cells and from cells pretreated with the acetylcholine analog carbachol (Cch), with the peptide hormone cholecystokinin (CCK) and with second messengers of hormone action such as cAMP and the diacylglycerol analog 12-O-tetradecanoyl phorbol-13-acetate (TPA). Ion and water influx rates in ZG and consequent swelling and lysis of granules was monitored by measuring changes in optical densities of ZG suspensions at 540 nm following additions of the electrogenic or electroneutral ionophores valinomycin and nigericin, respectively. The data show that both a Cl- conductance and an anion exchange pathway are present in the granule membrane. Both pathways are activated by pretreatment of isolated cells with CCK or of isolated permeabilised cells with cAMP, whereas only the Cl- conductance is increased by pretreatment with Cch or with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secretagogue and second messenger-activated Cl- permeabilities in isolated pancreatic zymogen granules. 256 Jan 64

Receptor occupation by a variety of Ca2+-mobilizing hormones, such as alpha 1-adrenergic agents, vasopressin and angiotensin II, causes a rapid phosphodiesterase-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate in the plasma membrane with the production of the water soluble compound myo-inositol-1,4,5-trisphosphate (IP3) and the lipophilic molecule 1,2-diacylglycerol (DG). This review summarizes the recent evidence obtained in the liver that defines the roles of these products as intracellular messengers of hormone action. Intracellular Ca2+ mobilization is mediated by IP3, which releases Ca2+ from a subpopulation of the endoplasmic reticulum, resulting in a rapid increase of the cytosolic free Ca2+ concentration ( [Ca2+]i). Further effects of receptor occupancy are inhibition of the plasma membrane Ca2+-ATPase, despite net Ca2+ efflux, and an increased permeability of the plasma membrane to extracellular Ca2+. The activation of the phospholipid-dependent protein kinase C by DG does not alter Ca2+ fluxes across the plasma membrane. In contrast to some secretory cells, a synergism between protein kinase C activation and increased [Ca2+]i is not observed in liver. Activation of protein kinase C profoundly inhibits the response to alpha 1-adrenergic agonists, with only minimal effects on the vasopressin response. It is concluded that in liver the two inositol-lipid messenger systems, IP3 and DG, exert their effects by essentially separate pathways.
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PMID:Inositol trisphosphate and diacylglycerol as intracellular second messengers in liver. 257 67

Interest in the inositol phospholipids was stimulated by the simultaneous discoveries that the products of hydrolysis of these lipids could serve as messengers to activate to synergistic signaling pathways in hormonally responsive cells, namely, inositol 1,4,5-trisphosphate which causes the release of Ca2+ from intracellular stores and diacylglycerol which promotes the activation of protein kinase C. At the same time, Berridge and co-workers introduced relatively simple approaches to study the inositol phospholipid cycle. These included the use of [3H]inositol to label the inositol metabolites, all of which are confined to this cycle, and of Li+ to decrease the rate of degradation of the inositol phosphates. Water-soluble inositol phosphates and chloroform-soluble inositol phospholipids could then be separated by solvent partition and the inositol phosphates further separated by use of an anion-exchange resin. However, the subsequent application of high-performance liquid chromatography as a separation technique indicated the existence of many isomers of the inositol phosphates formed by different pathways of dephosphorylation and phosphorylation. Mapping of these metabolic pathways may be substantially complete, but novel pathways may still be discovered. We review both old and new methods of analysis of the inositol phosphates for the measurement of mass and radioactivity. Although the complexity of the cycle sometimes demands the use of sophisticated methods of separation and rigorous identification, older and inexpensive methods may still be useful for some purposes.
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PMID:Methods for the analysis of inositol phosphates. 269 83


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