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)

Interactions between the different signaling roles of myo-inositol 1,4,5-trisphosphate and 1,2-diacylglycerol, the products of agonist-stimulated phosphatidylinositol 4,5-bisphosphate breakdown, are assessed in isolated rat hepatocytes. Measurements of the kinetics of accumulation of individual [3H]inositol phosphates after the addition of different Ca2+-mobilizing agonists in general support the role of inositol 1,4,5-trisphosphate as the second messenger responsible for release of sequestered intracellular Ca2+. Various agonists, when added at maximal concentrations, however, produce qualitatively and quantitatively different responses, which reflect varying abilities of the agonists to activate phospholipase C. Qualitative differences are revealed by a pronounced biphasic pattern to the Ins(1,4,5)P3 accumulation after vasopressin and phenylephrine stimulation, which is indicative of negative feedback. It is suggested that this effect is mediated by a partial diacylglycerol activation of protein kinase C, which in vitro causes an activation of inositol phosphate 5-phosphatase and hence promotes removal of Ins(1,4,5)P3 to Ins(1,4)P2. An alternative mechanism proposed by Biden and Wollheim (1986) of a secondary Ca2+ activation of Ins(1,4,5)P3 3-kinase is considered less likely as a general mechanism, since highly purified kinase prepared from rat brain shows only an inhibition by Ca2+. Glucagon, 8-Br-cAMP, and EGF induce small increases of Ins(1,4,5)P3 in hepatocytes, together with slower and smaller increases of cytosolic free Ca2+ than those produced by vasopressin or phenylephrine, with Ca2+ being mobilized from the same intracellular pools with each of the agonists. The Ca2+-mobilizing effect of glucagon, therefore, may be entirely due to a cAMP-dependent process, although a direct receptor-mediated activation of phospholipase C, as suggested by Wakelam et al. (1986), remains a possibility. The EGF receptor appears to be coupled to phospholipase C, presumably via a G-protein. It is speculated that the mechanism by which cAMP increases Ins(1,4,5)P3 levels in hepatocytes could either be by phosphorylation and inhibition of inositol phosphate 5-phosphatase or by phosphorylation and facilitation of the coupling between the G-protein and phospholipase C. When protein kinase C is maximally activated by pretreatment of hepatocytes with PMA, the stimulatory effects of phenylephrine, glucagon, 8-Br-cAMP, and EGF on the accumulation of inositol phosphates and increase of cytosolic free Ca2+ are largely inhibited.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms involved in receptor-mediated changes of intracellular Ca2+ in liver. 285 Jun 13

A widespread, and maybe universal, response to stimulation of alpha-adrenoceptors is inositol lipid hydrolysis: the receptor-coupled event is probably hydrolysis of phosphatidylinositol 4,5-bisphosphate. This reaction generates two second messenger molecules. Inositol 1,4,5-trisphosphate may be responsible for the intracellular mobilization of Ca2+ that has long been recognized as a major mediator of the effects of alpha-receptor activation. In addition, the released 1,2-diacylglycerol probably contributes to control of cell function through activation of protein kinase C.
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PMID:Inositol lipid breakdown as a step in alpha-adrenergic stimulus-response coupling. 285 18

The response of cells to many external stimuli requires a decoding process at the membrane to transduce information into intracellular messengers. A major decoding mechanism employed by a variety of hormones, neurotransmitters and growth factors depends on the hydrolysis of a unique inositol lipid to generate two key second messengers, diacylglycerol and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Here I examine the second messenger function of Ins(1,4,5)P3 in controlling the mobilization of calcium. We know most about how this messenger releases calcium from internal reservoirs but less is known concerning the entry of external calcium. One interesting possibility is that Ins(1,4,5)P3 might function in conjunction with its metabolic product Ins(1,3,4,5)P4 to control calcium entry through a mechanism employing a region of the endoplasmic reticulum as a halfway house during the transfer of calcium from outside the cell into the cytoplasm. The endoplasmic reticulum interposed between the plasma membrane and the cytosol may function as a capacitor to insure against the cell being flooded with external calcium. When stimulated, cells often display remarkably uniform oscillations in intracellular calcium. At least two oscillatory patterns have been recognized suggesting the existence of separate mechanisms both of which may depend upon Ins(1,4,5)P3. In one mechanism, oscillations may be driven by periodic pulses of Ins(1,4,5)P3 produced by receptors under negative feedback control of protein kinase C. The other oscillatory mechanism may depend upon Ins(1,4,5)P3 unmasking a process of calcium-induced calcium release from the endoplasmic reticulum. The function of these calcium oscillations is still unknown. This Ins(1,4,5)P3/calcium signalling system is put to many uses during the life history of a cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The Croonian lecture, 1988. Inositol lipids and calcium signalling. 290 30

We have investigated factors affecting the activation of phospholipase C in human platelets. Prior exposure of platelets to phorbol esters that stimulated protein kinase C inhibits the activation of phospholipase C in response to a variety of receptor-directed agonists, including alpha- and gamma-thrombin and thromboxane A2 analogues. Such activation has been assayed by measurements of accumulated InsP3 (including Ins(1,4,5)P3 and Ins(1,3,4)P3) and PtdOH. Inhibition is not overcome by Ca2+ ionophores, and substances that block or mimic Na+-H+ exchange neither block nor mimic these inhibitory effects. Cyclic AMP and cyclic GMP, other agents known to inhibit phospholipase C activation, do not accumulate in platelets exposed to phorbol esters. Although a portion of the effects of phorbol ester on InsP3 accumulation may be explained by 5-phosphomonoesterase activity, it is likely that more direct effects on phospholipase C are being exerted as well, and contribute the major inhibitory route. We have examined the susceptibility of adenylyl cyclase-associated Gi and 'Gp'-activated phospholipase C to inhibitory ADP-ribosylation by pertussis toxin-derived enzyme (S1 protomer) administered to saponin-permeabilized platelets. The effects of alpha-thrombin on adenylyl cyclase can be inhibited by up to 50% by S1, at which point inhibition of phospholipase C is barely detectable. Thromboxane A2 analogues, which do not affect adenylyl cyclase (Gi), stimulate phospholipase C; this effect is not impaired by S1. We therefore propose that the inhibitory effects of phorbol esters on the activation of phospholipase C are not mediated primarily by effects on Gi.
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PMID:Regulation of platelet phospholipase C. 290 40

Many hormones, neurotransmitters, and secretagogues act by increasing the intracellular free Ca2+ concentration in target cells. The initial event following binding of agonists to specific receptors in the plasma membrane involves a receptor-mediated activation of a guanosine nucleotide-binding protein (G protein), which induces a Ca2+-independent activation of phospholipase C. This novel, presently uncharacterized G protein is inactivated by pertussis toxin-catalyzed adenosine 5'-diphosphate ribosylation in some but not all cell types. Phospholipase C catalyzes the breakdown of inositol lipids, notably phosphatidylinositol 4,5-bisphosphate, with the production of inositol phosphates and 1,2-diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) is responsible for a rapid mobilization of intracellular Ca2+ by activating Ca2+ efflux from a subpopulation of the endoplasmic reticulum. The properties of this process are consistent with its being a ligand-activated ion channel with electrogenic Ca2+ efflux being charge-compensated by K+ influx. Sustained hormonal responses require extracellular Ca2+ and a prolonged elevation of the cytosolic free Ca2+. This is brought about by hormone-mediated changes of Ca2+ flux across the plasma membrane involving both an inhibition of Ca2+ efflux and an activation of Ca2+ influx. This review summarizes recent findings concerning the role of G proteins in receptor coupling to phospholipase C; the regulation of enzymes of phosphoinositide metabolism; the evidence for IP3 being a Ca2+-mobilizing second messenger and its mechanism of action; the formation of new inositol phosphates and their possible significance; the relation of intracellular Ca2+ mobilization and plasma membrane Ca2+ fluxes to the kinetics of the hormone-induced cytosolic free Ca2+ transient; and the possible roles of protein kinase C in influencing the hormone-mediated functional response.
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PMID:Role of inositol lipid breakdown in the generation of intracellular signals. State of the art lecture. 301 67

LPS and lipid A initiated enhanced hydrolysis of PIP2 in macrophages. When murine peritoneal macrophages were labeled with [2-3H]myoinositol and stimulated with either LPS or lipid A, a rapid (within 10 sec) rise in Ins(1,4,5)P3 was observed. The breakdown pattern of Ins(1,4,5)P3 was complex; this included breakdown of Ins(1,4,5)P3 and formation of Ins(1,3,4,5)P4 (approximately 10 to 30 sec), and ultimately formation of Ins(1,3,4)P3 (approximately 60 sec). Within 10 sec after treatment, LPS caused an average increase of about fourfold to fivefold in Ins(1,4,5)P3, which declined over 5 min. When the total isomers of InsP3 were measured, levels rose about twofold in response to LPS or to lipid A and remained elevated for as long as 5 min. Lipid A, in the concentration range of 0.1 to 10 micrograms/ml, induced elevated intracellular levels of Ca2+ as quantified by fluorescence with Quin 2 or with Fura 2. When single, adherent Fura 2-loaded macrophages were treated with lipid A, basal levels of calcium rose over 10 sec from approximately 55 nM to almost 600 nM. LPS, paradoxically, did not cause such substantial increases in intracellular calcium (i.e., increases of approximately 26 nM) when judged by Fura 2 fluorescence. LPS treatment led to enhanced phosphorylation of a characteristic set of proteins, similar to those induced by stimulating protein kinase C (PKC) with phorbol myristate acetate as previously reported. The enhanced phosphorylation of pp28, pp33, and pp67 in macrophages was evident by 15 min and optimal by 30 min. Taken together, these observations indicate that LPS and lipid A cause increased breakdown of phosphatidylinositol 4,5-bisphosphate, which led to enhanced intracellular levels of calcium and also to enhanced protein phosphorylation, presumably mediated by PKC. The data thus suggest that one major intracellular signal transduction mechanism, initiated by LPS and lipid A in macrophages, is the rapid breakdown of PIP2.
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PMID:Effects of bacterial lipopolysaccharide on the hydrolysis of phosphatidylinositol-4,5-bisphosphate in murine peritoneal macrophages. 303 44

Factors underlying the transience of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] accumulation following muscarinic stimulation of RINm5F cells were examined. Transience was not due to a protein kinase C-mediated stimulation of Ins(1,4,5)P3 dephosphorylation, since pretreatment of cells with tetradecanoyl-phorbol acetate (TPA) did not alter the rate of this conversion. However, preincubation with TPA did inhibit carbamoylcholine-stimulated Ins(1,4,5)P3 formation. In permeabilized cells, the conversion of Ins(1,4,5)P3 to inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] was slightly enhanced in the presence of TPA or cyclic AMP, but much more markedly by raising the Ca2+ concentration from 10(-7) M to 10(-6) or 10(-5) M. In intact cells the most rapid rate of accumulation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 occurred in the first 2 s following stimulation, whereas the levels of inositol 1,4-bisphosphate were not increased until after 5 s. This suggests that Ins(1,4,5)P3 kinase is chiefly responsible for the early disposal of Ins(1,4,5)P3 following cellular stimulation. The results are consistent with the proposal that the transient accumulation of Ins(1,4,5)P3 is due both to its enhanced metabolism via the Ca2+-calmodulin-sensitive Ins(1,4,5)P3 kinase, as well as a down-regulation of phosphatidylinositol 4,5-bisphosphate hydrolysis.
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PMID:Regulation of inositol 1,4,5-trisphosphate metabolism in insulin-secreting RINm5F cells. 304 62

The binding of a number of extracellular ligands (hormones, growth factors, neurotransmitters etc.) to their plasma membrane receptors causes hydrolysis of phosphatidylinositol bisphosphate to initiate the formation of two second messengers, inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and diacylglycerol, DAG. DAG has been shown to activate protein kinase C, whereas Ins(1,4,5)P3 induces the release of Ca2+ from an intracellular pool. This rapidly mobilizable, Ins(1,4,5)P3-sensitive Ca2+ store has until now been identified as the endoplasmic reticulum, ER. We demonstrate that this is untenable and provide evidence for the existence of an unrecognized organelle, the 'calciosome'. This conclusion is based on the following experimental evidence. (1) There is no correlation between the abundance of ER and the amount Ins(1,4,5)P3-sensitive Ca2+ release. (2) There is no correlation between ER markers and those for the Ca2+ store [Ins(1,4,5)P3 binding and sensitivity, Ca2+ uptake]. (3) A protein similar to striated muscle calsequestrin, CS, has been identified in microsomal fractions from a number of tissues; it copurifies with markers of the Ca2+ store, but not with those of ER. (4) Subcellular localization of the CS-like protein by electron microscopy reveals that in all cells so far analysed this protein is localized in small, membrane-enclosed structures, calciosomes, which are also stained by an anti-Ca2+-ATPase antibody. Calciosomes appear to be morphologically distinct from any other known cell organelle. (5) Although they stain different portions of the calciosomes (membrane and lumen, respectively), anti-Ca2+-ATPase and anti-CS antibodies do not recognize any antigen in ER cysternae; antibodies directed against known components of ER do not bind to calciosomes.
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PMID:The Ins(1,4,5)P3-sensitive Ca2+ store of non-muscle cells: endoplasmic reticulum or calciosomes? 306 19

Inositol 1,4,5-trisphosphate induces aggregation and the release of [3H]5-hydroxytryptamine from human platelets rendered permeable with saponin. This action of inositol 1,4,5-trisphosphate is associated with a significant formation of thromboxane B2, activation of phospholipase C, and phosphorylation of 20,000- and 40,000-dalton proteins, which are the substrates for myosin light chain kinase and protein kinase C, respectively. All of these responses are blocked by the cyclooxygenase inhibitors indomethacin and aspirin and the dual cyclooxygenase and lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C). These data indicate that platelet activation by inositol 1,4,5-trisphosphate is initiated by the mobilization of Ca2+, which leads to phospholipase A2 activation. The thromboxanes and endoperoxides that are subsequently generated then induce activation via cell surface receptors.
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PMID:Inositol 1,4,5-trisphosphate induces aggregation and release of 5-hydroxytryptamine from saponin-permeabilized human platelets. 308 84

Receptor-mediated breakdown of PtdIns(4,5)P2 produces two cellular signals, Ins(1,4,5)P3, which can release intracellular Ca2+, and diacylglycerol, which activates a Ca2+- and phospholipid-dependent protein kinase (protein kinase C). This study assesses the significance of protein kinase C in relation to phenylephrine- and vasopressin-induced Ca2+ mobilization in hepatocytes. Phorbol ester (4 beta-phorbol-12-myristate-13-acetate), which can directly activate protein kinase C, had no effect either on Ca2+ efflux from the cell (measured with arsenazo III) or on Ca2+ influx (measured with Quin-2), processes which are inhibited and stimulated, respectively, by both phenylephrine and vasopressin. No evidence of synergism between phorbol ester pretreatment of hepatocytes and the Ca2+ ionophore (ionomycin)-mediated effects on the increase of cytosolic free Ca2+ and phosphorylase activation could be obtained. These findings suggest that protein kinase C is not obligatorily involved in the regulation of hepatocyte Ca2+ fluxes. Pretreatment of hepatocytes with phorbol ester (PMA) or 1-oleoyl-2-acetylglycerol totally inhibited the effects of phenylephrine in elevating the cytosolic free Ca2+; half-maximal inhibitory effects occurred at PMA and 1-oleoyl-2-acetylglycerol concentrations of 1 ng/ml and 12 micrograms/ml, respectively. In contrast, pretreatment with PMA had a much smaller effect on Ca2+ mobilization induced by vasopressin. These observations suggest that protein kinase C may be involved in "down-regulation" of the alpha 1-receptor in hepatocytes and may thus exert a negative influence on the Ca2+-signalling pathway.
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PMID:Differential effects of phorbol ester on phenylephrine and vasopressin-induced Ca2+ mobilization in isolated hepatocytes. 391 20


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