Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the mammalian nervous system, serotonin (5-hydroxytryptamine) binds to distinct cell surface receptor subtypes that are defined by their ligand binding and effector-coupling properties. The 5HT1c receptor is a G-protein coupled receptor that stimulates phospholipase C-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C. By using somatic cell hybrid analysis and FISH, we have mapped the HTR1C locus to the human X chromosome, band q24 and to the mouse X chromosome region D-F4. Comparison of these map positions offers new insights into the evolution of human and murine X chromosomes. Since HTR1C is expressed in certain parts of the central nervous system and abnormal function of the serotoninergic system has been implicated in affective disorders, obsessive-compulsive disorder and epilepsy, establishing the precise map position of HTR1C is an important first step toward evaluating this locus as a candidate for mutations in these syndromes and in X-linked mental disorders.
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PMID:Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). 130 5

1. The presence of adenosine receptors linked to adenylate cyclase activity and their functional role in calcium-evoked 5-hydroxytryptamine (5-HT) release was investigated in rat basophilic leukaemia (RBL) cells, a widely used model for studying the molecular mechanisms responsible for stimulus-secretion coupling. 2. In [3H]-5-HT-loaded cells triggered to release by the calcium ionophore A23187, a biphasic modulation of 5-HT secretion was induced by adenosine analogues, with inhibition of stimulated release at nM and potentiation at microM concentrations, suggesting the presence of adenosine receptor subtypes mediating opposite effects on calcium-dependent release. This was also confirmed by results obtained with other agents interfering with adenosine pharmacology, such as adenosine deaminase and the non-selective A1/A2 antagonist 8-phenyl-theophylline. 3. Similar biphasic dose-response curves were obtained with a variety of adenosine analogues on basal adenylate cyclase activity in RBL cells, with inhibition and stimulation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) production at nM and microM concentrations, respectively. The rank order of potency of adenosine analogues for inhibition and stimulation of adenylate cyclase activity and the involvement of G-proteins in modulation of cyclic AMP levels suggested the presence of cyclase-linked A1 high-affinity and A2-like low-affinity adenosine receptor subtypes. However, the atypical antagonism profile displayed by adenosine receptor xanthine antagonists on cyclase stimulation suggested that the A2-like receptor expressed by RBL cells might represent a novel cyclase-coupled A2 receptor subtype.4. Micromolar concentrations of adenosine analogues could also increase inositol phospholipid hydrolysis and inositol tris-phosphate formation in both unstimulated cells and in cells triggered to release by the calcium ionophore. The stimulation was constant, small and additive to that exerted by the calcium ionophore.5. It is concluded that RBL cells express both A1 and A2-like adenosine receptors which exert opposite effects on 5-HT release and intracellular cyclic AMP levels. However, besides modulation of cyclic AMP levels, additional transduction pathways, such as modulation of phospholipase C activity, may contribute to the release response evoked by adenosine analogues in this cell-line.
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PMID:Adenosine receptors in rat basophilic leukaemia cells: transductional mechanisms and effects on 5-hydroxytryptamine release. 131 28

Catecholamines acting through beta 1- and beta 2-adrenergic receptors cause positive inotropic and chronotropic effects in the human heart. However, recent evidence suggests that in the human heart other receptor systems can also affect heart rate and contractility. Positive inotropic effects can be mediated by receptor systems acting through accumulation of intracellular cyclic adenosine monophosphate (cAMP; Gs-protein-coupled receptors such as 5-hydroxytryptamine(5-HT)4-like, histamine H2, and vasoactive intestinal peptide) or by receptor systems acting independently of cAMP, possibly through the phospholipase C/diacylglycerol/inositol-1,4,5-trisphophate pathway (such as alpha 1-adrenergic, angiotensin II, and endothelin). In the nonfailing human heart, activation of all these receptor systems induces only submaximal positive inotropic effects compared with those caused by beta-adrenergic receptor stimulation, indicating that in humans the cardiac beta-adrenergic receptor/Gs-protein/adenylate cyclase pathway is the most powerful mechanism to increase heart rate and contractility. However, the human heart contains only a few spare receptors for beta-adrenergic receptor-mediated positive inotropic effects and nearly all beta-adrenergic receptors are needed to cause maximal inotropic effects. Thus any decrease in the number of beta-adrenergic receptors will automatically lead to a reduction in functional responsiveness of beta-adrenergic receptors. In chronic heart failure the number and responsiveness of cardiac beta-adrenergic receptors are reduced, presumably because of the enhanced sympathetic drive to the heart and hence endogenous down-regulation by an elevated release of (cardiac-derived) norepinephrine, and this loss in cardiac beta-adrenergic receptor function is strongly related to the severity of the disease. However, beta 1- and beta 2-adrenergic receptors are differentially changed in different forms of heart failure. In dilated cardiomyopathy and possibly in aortic valve disease the number of cardiac beta 1-adrenergic receptors is selectively reduced without alteration in the number of beta 2-adrenergic receptors (although beta 2-adrenergic receptors become somewhat uncoupled). In ischemic cardiomyopathy, mitral valve disease, and possibly tetralogy of Fallot, the number of both beta 1- and beta 2-adrenergic receptors is concomitantly decreased. Because of the lack of a substantial receptor reserve, such a decrease in the number of beta-adrenergic receptors is accompanied by reduced inotropic and chronotropic responses to beta-adrenergic receptor stimulation in vitro and in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor systems affecting force of contraction in the human heart and their alterations in chronic heart failure. 135 62

1. The effect of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), on human platelets has been investigated. 2. Okadaic acid exerts a general increase in phosphorylation of platelet proteins but did not induce aggregation or secretion of 5-hydroxytryptamine (5-HT). Okadaic acid, however, did inhibit thrombin-induced functional responses. 3. Maximally effective concentrations of prostacyclin, to elevate adenosine 3'-5'-cyclic monophosphate (cyclic AMP), or phorbol dibutyrate, to activate protein kinase C, inhibited the formation of inositol phosphates by thrombin by approximately 60%. When used in combination, prostacyclin and phorbol dibutyrate reduced the levels of inositol phosphates induced by thrombin to 11%. 4. Okadaic acid (1 microM) decreased thrombin-induced formation of inositol phosphates by approximately 55% and increased the inhibitory action of prostacyclin or phorbol dibutyrate. Okadaic acid had no further effect when prostacyclin and phorbol dibutyrate were used in combination. 5. These results suggest that protein kinases A and C act to inhibit phospholipase C by distinct mechanisms and that their action is reversed by PP1 and/or PP2A.
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PMID:Okadaic acid inhibits activation of phospholipase C in human platelets by mimicking the actions of protein kinases A and C. 162 49

The cloned 5-HT1A receptor, stably expressed in HeLa cells, has been shown to mediate the effects of 5-hydroxytryptamine (5-HT) to inhibit cAMP formation and to stimulate the hydrolysis of phosphatidylinositol. Both responses were found to be pertussis toxin sensitive. We have examined these two responses in membranes derived from these cells and show that the 5-HT1A receptor can directly regulate the activity of adenylyl cyclase and phospholipase C in response to agonist. In order to examine whether the same or distinct guanine nucleotide-binding regulatory protein(s) (G protein) are involved in these two signal transduction pathways, we used anti-peptide antibodies recognizing the alpha-subunits of Gi1, Gi2, Gi3 as specific tools, since these pertussis toxin substrates are expressed in HeLa cells. These antibodies have previously been shown to prevent receptor-G protein coupling by binding to the regions of G proteins which are putatively involved in interaction with receptors. Our results indicate that the Gi proteins, but preferentially Gi3, mediate the effects of 5-HT both to inhibit adenylyl cyclase and to stimulate phospholipase C. These findings demonstrate that the same receptor interacting with the same G protein can regulate several distinct effector molecules.
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PMID:Dual coupling of the cloned 5-HT1A receptor to both adenylyl cyclase and phospholipase C is mediated via the same Gi protein. 178 5

During culture, smooth-muscle cells obtained from rabbit basilar arteries were examined for contractile activity by means of differential interference microscopy with a video analysis system (digital imaging microscopy system). This system proved useful for observing the contraction and ultrastructural changes of the living cells. Hemolysate-treated cells showed augmented responses to 5-hydroxytryptamine and leukotriene C4, but not to KCl. This augmented response diminished gradually during the culture period. Both a phospholipase C blocking agent, 2-nitro-4-carboxyphenyl-n,n-diphenylcarbamate (NCDC), and a myosin light chain kinase blocking agent, 1-(5-chloronaphthalenesulfonyl)-1H-hexahydro-1,4-diazepine (ML-9), suppressed this augmented response. Protein kinase C activity of the cells, as measured by Western blot analysis, did not increase during the period of culture with hemolysate. The results obtained suggest that hemolysate had the following effects on the cells: 1) acute but gradual contraction of the cells; 2) augmentation of cellular responses to vasoactive agents; and 3) progressive contraction and morphological alteration of the cells. Possible mechanisms by which hemolysate exerts these effects are discussed, taking into consideration the interrelationship between these effects.
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PMID:Altered reactivity of hemolysate-treated cultured smooth-muscle cells from rabbit basilar artery determined by digital imaging microscopy. 204 25

5-Hydroxytryptamine (5-HT) stimulates the rate and force of cardiac contraction. However, the molecular mechanisms of 5-HT actions on the heart are unknown. We examined effects of 5-HT on phospholipase C-mediated hydrolysis of phosphoinositides and its regulation in cultured fetal mouse ventricular myocytes labeled with [3H]inositol. Accumulation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate was assessed after stimulation with 5-HT, catecholamines, and AlF4-. Inositol bisphosphate and trisphosphate reached a peak at 15 minutes by 5-HT stimulation and at 30 minutes by AlF4- stimulation. Inositol monophosphate accumulated linearly for at least 30 minutes in the presence of LiCl. The 5-HT effect was dose dependent, and the threshold concentration was 0.1 microM with the half-maximum effective concentration of 1 microM. Ketanserin in nanomolar concentrations inhibited the phospholipase C reaction by 100 microM 5-HT with the half-maximum inhibitory concentration of 0.5 nM. Pertussis toxin (100-1,000 ng/ml) did not influence the phospholipase C reaction by 5-HT, but it partially inhibited the reaction by AlF4-. Protein kinase C-activating phorbol esters like 12-O-tetradecanoylphorbol 13-acetate (TPA) and phorbol 12,13-dibutyrate, but not 4 alpha-phorbol 12,13-didecanoate, which is inactive for protein kinase C, completely inhibited the reaction by 5-HT; TPA showed 30% inhibition on the reaction by AlF4-. The magnitude of accumulated inositol phosphates by AlF4- was at least several times greater than that by 5-HT. Norepinephrine- and epinephrine-stimulated phospholipase C reactions were completely abolished by prazosin. These results suggest that 5-HT directly stimulates phospholipase C-mediated hydrolysis of phosphoinositides through 5-hydroxytryptamine-2 (5-HT2) receptors in the ventricular myocytes and that this reaction is negatively regulated by protein kinase C. 5-HT2 receptors may be coupled to phospholipase C via a pertussis toxin-insensitive GTP-binding protein in the myocytes.
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PMID:5-Hydroxytryptamine induces phospholipase C-mediated hydrolysis of phosphoinositides through 5-hydroxytryptamine-2 receptors in cultured fetal mouse ventricular myocytes. 216 Aug 68

1. Phorbol esters are known to inhibit phospholipase C-mediated hydrolysis of membrane phosphoinositide. This inhibition is attributed to participation of protein kinase C (PKC) in a negative-feedback control of phosphoinositide metabolism. We have tested this hypothesis by using different types of activators and inhibitors of PKC. 2. Phorbol-12,13-dibutyrate (PDB) inhibited the stimulatory effect of acetylcholine (ACh) on [3H]inositol monophosphate ([3H]IP) formation in cultured sympathetic neurons of the chick embryo and adrenal medulla of the rat. 3. Acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) activated neuronal PKC by 3- to 8-fold. The extent of PKC activation by 100 microM-ACh was comparable to that of 100 nM-PDB. Activation of PKC by pre-incubation of sympathetic neurons with ACh (or 5-HT) did not inhibit the stimulatory effects of ACh (or 5-HT) on [3H]IP formation. 4. Pre-treatment of sympathetic neurons or adrenal medulla with a PKC inhibitor H7 (1-(5-isoquinolinyl-sulphonyl)-2-methyl-piperazine) almost completely blocked activation of the enzyme induced by PDB, ACh or 5-HT. However, blockade of PKC did not prevent the inhibitory effects of PDB on ACh-induced [3H]IP formation. 5. Vasoactive intestinal polypeptide (VIP) and muscarine induced catecholamine secretion from the perfused adrenal medulla via formation of inositol-1,4,5-tirisphosphate (IP3). Phorbol-12,13-dibutyrate decreased muscarine-induced catecholamine secretion. However, activation of PKC by VIP had no effect on muscarine-induced catecholamine secretion and vice versa. 6. These results suggest that PKC is not negatively coupled to phosphoinositide hydrolysis in sympathetic neurons and chromaffin cells. Phorbol esters must have targets other than PKC to interfere with the phosphoinositide hydrolysis.
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PMID:Phosphoinositide hydrolysis is not negatively regulated by protein kinase C in the peripheral tissues of rat and chick. 217 Jun 29

The mechanisms of 5-hydroxytryptamine (5-HT)-induced contraction of rat aorta were investigated in vitro. The 5-HT-induced contraction could be analyzed into two distinct components (phasic and tonic) by the use of appropriate inhibitors; nifedipine, an inhibitor of voltage-dependent Ca++ channels, inhibited only the phasic component of 5-HT-induced contraction while totally blocking the KCl-induced contraction. 2-Nitro-4-carboxyphenyl-N,N-diphenylcarbamate, an inhibitor of phospholipase C, inhibited the tonic components of 5-HT-induced contraction as well as the 5-HT-induced stimulation of phosphoinositide hydrolysis in rat aorta. This component of contraction was mimicked by a protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate. These results suggest that 5-HT2 receptors differentially regulate a voltage-dependent Ca++ channel and phospholipase C activity; the voltage-dependent Ca++ channel is involved in the phasic component of contraction whereas the phosphoinositide hydrolysis that results in the activation of protein kinase C and calcium mobilization by inositol triphosphate plays a physiologically important role in the tonic component of the aortic contraction.
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PMID:Phasic and tonic components in 5-HT2 receptor-mediated rat aorta contraction: participation of Ca++ channels and phospholipase C. 241 May 94

mRNAs for isozymes of phospholipase C (PLC) were localized in rat brain by in situ hybridization with oligonucleotide probes for PLC isozymes I, II, and III of Rhee's group [Suh, P.-G., Ryu, S. H., Moon, K. H., Suh, H. W. & Rhee, S. G. (1988) Proc. Natl. Acad. Sci. USA 85, 5419-5423 and (1988) Cell 54, 161-169], and isozyme I of Bennett and Crooke [Bennett, C. F., Balcarek, J. M., Varrichio, A. & Crooke, S. T. (1988) Nature (London) 334, 268-270], which we designate PLC-A. The isozymes displayed different localizations. PLC-A mRNA was highest in the mitral cell layer of the olfactory bulb, choroid plexus, hippocampus and dentate gyrus, magnocellular hypothalamic nuclei, rostral raphe nuclei, and cerebellar Purkinje cells. PLC-I was highest in the internal granular cell layer of the olfactory bulb, cerebral cortex, caudate, nucleus of the lateral olfactory tract, reticular nucleus of thalamus, hippocampus and dentate gyrus, and granule cell layer of the cerebellum. PLC-II had a more widespread distribution, with relatively high levels in the internal granular layer of the olfactory bulb, hippocampus and dentate gyrus, and cerebellar Purkinje and granule cells. PLC-III label was low throughout the brain. These distributions suggest selective coupling of individual PLC isozymes with particular postsynaptic receptors. PLC-A may be preferentially associated with 5-hydroxytryptamine 1C receptors, vasopressin V1 receptors, and a subtype of glutamate receptors. PLC-I may be linked to muscarinic m1 and m3 receptors as well as other receptors. The distribution of PLC-II mRNA resembles that of src protooncogene, with which it displays sequence homology.
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PMID:Brain phospholipase C isozymes: differential mRNA localizations by in situ hybridization. 246 62


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