Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Phosphoinositide hydrolysis is not negatively regulated by protein kinase C in the peripheral tissues of rat and chick. 217 Jun 29

1. Exogenous arachidonic acid (AA) inhibits the protein phosphatase that dephosphorylates smooth muscle myosin, thus sensitizing the contractile response to Ca2+; it also inhibits voltage-gated Ca2+ channels in smooth muscle. The purpose of the present study was to determine whether endogenous AA is increased by agonists in a manner consistent with its role as a messenger regulating myosin phosphatase and Ca2+ channels. Both AA and diacylglycerol (DAG) were measured in [3H]AA-labelled intact and permeabilized (with staphylococcal alpha-toxin) rabbit femoral arteries stimulated with the alpha 1-adrenergic agonist phenylephrine (PE) (intact and permeabilized smooth muscles) or by guanosine-5'-O-(3-thiotriphosphate (GTP gamma S; permeabilized smooth muscles in which the [Ca2+] was maintained constant). Arachidonic acid mass was determined with gas chromatography and mass spectrometry (GC-MS). 2. In intact smooth muscle, PE increased both AA and DAG levels significantly, to 210 and 145% of baseline values, respectively. Another Ca2+-sensitizing agent, the thromboxane analogue U46619, caused a similar increase in AA and DAG levels in rabbit pulmonary artery. 3. In permeabilized smooth muscle at constant [Ca2+](pCa 6.5) GTP gamma S-induced AA and DAG release preceded force development and GTP gamma S (50 microM, 10 min) increased AA mass to 61-88 microM. 4. Phorbol-12,13-dibutyrate (PDBu), another Ca2+-sensitizing agent, also increased both AA and DAG levels in permeabilized smooth muscle at pCa 6.5, whereas the inactive analogue, 4 alpha-phorbol, did not have a Ca2+-sensitizing effect, nor did it increase AA and DAG levels. 5. In the virtual absence of Ca2+ (pCa > 8) GTP gamma S also increased AA and DAG levels by 3.5- and 1.6-fold, respectively. The effect of free Ca2+ itself on AA and DAG release was modest in the physiological range (pCa 7.0 to pCa 6.0), but pCa 4.5 caused an approximately 3- to 4-fold increase in AA and DAG levels, compared with the levels at pCa 8. In permeabilized ileum smooth muscle maintained at constant [Ca2+] (pCa 6.0), carbachol also significantly increased AA to 1.75 times its original value within 1 min of its application. 6. Our results are consistent with, although do not prove, the roles of AA and DAG as second and/or co-messenger(s) in smooth muscle, while the increases in AA and DAG levels induced by PDBu raise the possibility that they contribute to some of the cellular effects of phorbol esters.
 ...
PMID:Arachidonic acid and diacylglycerol release associated with inhibition of myosin light chain dephosphorylation in rabbit smooth muscle. 756 27

The effects of adenosine on hippocampal neurons were examined by patch-clamp recording and Ca2+ imaging using fura-2 fluorescence. In the whole-cell patch-clamp configuration, adenosine evoked outwardly rectifying K+ currents in a dose-dependent manner. These currents were not inhibited by a nonselective P1 purinoceptor antagonist or selective adenosine A1, A2A receptor antagonists and moreover, selective adenosine A1, A2A receptor agonists evoked no current. In contrast, P2 purinoceptor agonists produced similar outward currents with the order of potency: ADP > or = 2-methylthio ATP > ATP > adenosine >> AMP. No response was obtained to UTP, alpha, beta-methylene ATP or beta, gamma-methylene ATP. The intracellular perfusion of a broad G-protein inactivator, guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), abolished adenosine-evoked currents, whereas a Gi/Go-protein inhibitor, pertussis toxin, had no effect. Furthermore, the currents were blocked by a phospholipase C inhibitor, neomycin, or specific protein kinase C inhibitors, GF109203X (bisindolyl maleimide, C25H24N4O2) and protein kinase C inhibitor peptide. In the cell-attached patch-clamp configuration, adenosine elicited single-channel currents with two major kinds of slope conductances. Likewise, application of adenosine outside the patch electrode again produced single-channel currents with same conductances. A potent protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), induced single-channel currents in a fashion that mimics the effect of adenosine. The evoked currents were blocked by GF109203X. In addition, adenosine enhanced intracellular free Ca2+ concentration ([Ca2+]i). This [Ca2+]i increase was inhibited by GDP beta S or neomycin, but was not affected by pertussis toxin. These results, thus, suggest that adenosine activates the K+ channel and enhances cytosolic Ca2+ release via a P2Y purinoceptor linked to a pertussis toxin-insensitive G-protein, which is involved in a phospholipase C-mediated phospholipid-signaling pathway.
 ...
PMID:Adenosine activates the K+ channel and enhances cytosolic Ca2+ release via a P2Y purinoceptor in hippocampal neurons. 881 2

The modulatory role of protein kinase C on phospholipase A2, activation of which had been suggested to result in acetylcholine release from cholinergic neurons, was studied in longitudinal muscle preparations with the myenteric plexus of guinea pig ileum. The relationship of muscarinic autoinhibition to the modulation was also examined. Phorbol-12,13-dibutyrate (PDBu), an activator of protein kinase C, dose-dependently increased spontaneous and electrical field stimulation-induced acetylcholine releases from the preparation. The inhibitors of protein kinase C, staurosporine and calphostin C, inhibited the stimulatory effects of PDBu, but neither inhibitor affected spontaneous or electrical field stimulation-induced acetylcholine release in the absence of PDBu. On the other hand, atropine significantly increased electrical field stimulation-induced release by blocking a muscarinic autoinhibitory mechanism. Under the auto-inhibition blocked condition, U73122, an inhibitor of phospholipase C, and staurosporine significantly inhibited the effect of atropine on electrical field stimulation-induced release. An inhibitor of phospholipase A2, mepacrine, inhibited PDBu-induced acetylcholine release and also inhibited the effect of atropine on electrical field stimulation-induced release. An activator of phospholipase A2, melittin, and a product of the phospholipase, arachidonic acid, increased the spontaneous and electrical field stimulation-induced releases. These results suggest that the phospholipase C-protein kinase C system modulates acetylcholine release from cholinergic neurons by activating phospholipase A2 in the myenteric plexus of guinea pig ileum, and the activation of muscarinic autoreceptor may negatively modulate acetylcholine release at a point upstream of the system.
 ...
PMID:Muscarinic autoinhibition and modulatory role of protein kinase C in acetylcholine release from the myenteric plexus of guinea pig ileum. 924 23