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)

At least two signal-generating systems are involved in the actions of various hormonal factors in human platelets--the adenylate cyclase system and the phosphoinositide-metabolizing pathway. The formation of cyclic AMP (cAMP) by the adenylate cyclase system--consisting of the catalyst itself, the Ns and Ni proteins, and various hormone receptors--is stimulated by prostaglandins and adenosine, and is inhibited by alpha 2-adrenergic agonists, ADP, vasopressin, platelet-activating factor, and thrombin. On the other hand, the formation of inositol trisphosphate and diacylglycerol by the phosphoinositide-metabolizing pathway is stimulated by some of the latter agents, particularly by thrombin. There are apparently several mutual interactions between these two signal-generating systems. On the one hand, increases in the level of cAMP inhibit the formation of inositol phosphates and diacylglycerol. It is presently unclear whether this inhibitory effect of cAMP is due to a direct action at the phospholipase C itself or to an indirect mechanism, for example, a depletion of the substrate of the enzyme. On the other hand, protein kinase C, which is activated by diacylglycerol, largely interferes with the adenylate cyclase system. This kinase, when activated by diacylglycerol or phorbol esters, apparently phosphorylates the guanine nucleotide-binding alpha-subunit of Ni, which results in an impairment or loss of the inhibitory hormonal signal transduction to the adenylate cyclase. Thus, available evidence indicates that the two signal-generating systems present in platelet membranes are not completely separated, and furthermore suggests that they may even be causally related to each other.
J Cardiovasc Pharmacol 1986
PMID:Interactions between the hormone-sensitive adenylate cyclase system and the phosphoinositide-metabolizing pathway in human platelets. 243 28

Thrombin-induced aggregation and serotonin release were markedly enhanced in platelets from spontaneously hypertensive rats (SHR) when compared to normotensive Wistar-Kyoto (WKY) controls. Since phosphoinositides are involved in calcium-mediated platelet responses, the metabolism of these lipids was investigated in SHR and WKY rats by using 32P-labeled quiescent platelets. In unstimulated cells, both the rate and extent of 32P incorporation into individual inositol-containing phospholipids and phosphatidic acid (PA) were identical in SHR and WKY rats. This suggests that the pool size and basal turnover of phosphoinositides did not differ between the two strains. In contrast, early thrombin-induced phosphoinositide metabolism, when monitored as changes in 32P-PA, was significantly higher in SHR than in WKY rats. Following thrombin stimulation, 32P-PA formation likely reflects the initial agonist-receptor interaction; therefore, our results suggest that phospholipase C activity is enhanced in SHR platelets. Thus, it can be postulated that the observed hypersensitivity of SHR phospholipase C may play a role in the overall alteration of cell calcium handling and hence in the SHR platelet response.
J Cardiovasc Pharmacol 1988
PMID:Relationship between enhanced phosphoinositide turnover and cellular responses in platelets from spontaneously hypertensive rats. 245 17

Intercellular signaling between the endothelial cell (EC) and vascular smooth muscle (VSM) is an important determinant of vasomotor tone. We evaluated mechanisms of action of EC-derived constrictors on VSM using conditioned medium from bovine aortic ECs in culture (EC-CM) or endothelin-1 (ET-1), and isolated coronary arteries or cultured VSM cells. EC-CM enhanced Ca2+ uptake into monolayers of rat aortic VSM and elicited sustained contractions in isolated coronary vessels in a time- and dose-dependent manner. The enhanced Ca2+ uptake and contractions were markedly attenuated by the Ca2+ channel antagonists bepridil, verapamil, and nitrendipine. EC-CM and ET-1 resulted in VSM membrane depolarization and increased excitability to electrical stimulation that was blocked by verapamil. ET-1 and EC-CM induced a dose-dependent increase in steady-state [Ca2+]i in Fura-2-loaded rat VSM cells. Most VSM responded with a rapid and transient increase in [Ca2+]i while others lacked only the transient phase. The elevated poststimulus [Ca2+]i level appeared to precede the influx of extracellular Ca2+ and contraction. EC-CM and ET-1 also resulted in time- and concentration-dependent increases in inositol monophosphate (IP) formation in rat aorta that paralleled the development of isometric force. We propose a biphasic mechanism in which the stable constrictors present in EC-CM elicit a rapid, phospholipase C-mediated mobilization of intracellular Ca2+ accompanied by or coupled to a sustained influx of extracellular Ca2+ through voltage-dependent channels.
J Cardiovasc Pharmacol 1989
PMID:Endothelial cell-derived vasoconstrictors: mechanisms of action in vascular smooth muscle. 247 25

The newly described peptide, endothelin-1 (ET-1), causes profound vasoconstriction, but the pathways of transmembrane signaling remain unclear. We demonstrate that in glomerular mesangial cells, smooth muscle-like vascular pericytes, ET-1 elevates intracellular Ca2+ ([ Ca2+]i) by activating the phosphoinositide cascade. ET-1 increased [Ca2+]i in two distinct kinetic patterns. Concentrations of 0.1-10.0 pM ET-1 caused a slow but sustained increase in [Ca2+]i that was insensitive to voltage-gated Ca2+ channel blockade but dependent on extracellular Ca2+. In contrast, ET-1 greater than or equal to 0.1 nM evoked a rapid, transient increase in [Ca2+]i followed by a lesser, sustained increase. Only the sustained increment of [Ca2+]i required extracellular Ca2+, but both phases were unaffected by Ca2+ channel blockade. The transient increase in [Ca2+]i resulted from activation of phosphoinositide-specific phospholipase C to release inositol trisphosphate (IP3), which mobilizes Ca2+ from intracellular stores. ET-1 also stimulated amiloride-inhibitable Na+/H+ exchange, causing cytosolic alkalinization. Thus, the phosphoinositide cascade probably mediates some biological functions of ET-1, including possibly contraction via pharmacomechanical coupling.
J Cardiovasc Pharmacol 1989
PMID:Endothelin-1 activates the phosphoinositide cascade in cultured glomerular mesangial cells. 247 34

Angiotensin II (Ang II) stimulation of vascular smooth muscle results in a myriad of intracellular signals that interact to produce the final physiologic response of the cell. One of the earliest documented events following incubation of these cells with Ang II is the rapid, phospholipase C-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate to yield two second messengers, inositol trisphosphate and diacylglycerol. Inositol trisphosphate releases calcium from nonmitochondrial intracellular storage sites, while diacylglycerol activates protein kinase C. Ang II also stimulates calcium influx and increases calcium efflux for the duration of the stimulus, as well as causing a biphasic change in intracellular pH. The delayed alkalinization is a consequence of enhanced Na+/H+ exchange. These signals then interact to modify the targets of phospholipase C, and result in phosphorylation of numerous cytoplasmic and cytoskeletal proteins. Thus, the signaling events induced by Ang II are complex, and dynamically interact to produce a constantly changing response for the duration of the stimulus.
J Cardiovasc Pharmacol 1989
PMID:Angiotensin II stimulation of vascular smooth muscle. 247 21

The extracellular Ca2+ dependence of agonist stimulation of vascular smooth muscle (VSM) has been investigated in rat cultured aortic smooth muscle cells (SMCs) and isolated mesenteric resistance vessels (MRVs). Agonists such as [Arg8]vasopressin (AVP), angiotensin II (Ang II), and adenosine-5'-triphosphate (ATP) stimulated 45Ca2+ entry into the SMCs that was (a) independent of the extent to which the membranes were polarized, and (b) was not inhibited by organic Ca2+ channel antagonists. Measuring the intracellular Ca2+ concentration [( Ca2+]i) after stimulation with agonists revealed a rapid increase of [Ca2+]i, which was followed by a sustained rise that was insensitive to Ca2+ antagonists. In Ca2+-free medium, only the initial peak of [Ca2+]i was still observed, but the sustained response to the agonists disappeared completely. This observation indicates that the sustained elevation seen in Ca2+-containing medium was the consequence of agonist-induced Ca2+ entry. In MRVs, a corresponding Ca2+-antagonist-insensitive, agonist (norepinephrine and AVP)-induced tonic tension was also identified. Moreover, agonists were able to induce sustained tension in the MRVs regardless of whether the membrane was normally polarized or was previously depolarized (80 mM K+) upon their administration. The agonist-stimulated 45Ca2+ entry in the SMCs could be blocked by the multivalent cations La3+, Cd2+, Mn2+, Co2+, Ni2+, and Mg2+ (in this order of potency). Depolarization-induced 45Ca2+ influx was inhibited by these cations in the same order of potency, but was significantly more sensitive to Cd2+ and significantly less sensitive to La3+ than that stimulated by agonists. Treatment with 2-nitro-4-carboxyphenyl-N,N-diphenyl-carbamate (NCDC, a proposed inhibitor of phospholipase C) reduced both the agonist-induced 45Ca2+ influx and the sustained elevation of [Ca2+]i in the SMCs. NCDC also abolished both contraction and depolarization induced by agonists in the MRVs. The kinase C stimulator phorbol-12-myristate-13-acetate (PMA) inhibited the agonist-induced 45Ca2+ influx and sustained increase in [Ca2+]i in the SMCs, whereas the kinase C inhibitor staurosporine had no effect. In the MRVs, in contrast, PMA had no influence on agonist-induced contractions. Staurosporine (1 microM), however, completely prevented these contractions, as did NCDC, but, unlike NCDC, it did so without affecting the agonist-induced depolarization. These data support an important role of receptor-operated Ca2+-permeable channels in VSM activation by agonists and suggest that these channels may be controlled by intracellular enzymic pathways and second messenger systems.
J Cardiovasc Pharmacol 1989
PMID:Receptor-operated calcium-permeable channels in vascular smooth muscle. 247 25

A previous study revealed that elevation of platelet cyclic GMP induced by a pharmacological activator of soluble guanylate cyclase, 3-morpholinosydnonimine (SIN-1), induced a major inhibition of Ca2+ influx caused by thrombin, as detected by monitoring the fluorescence of the Ca2+ indicator quin-2. In contrast, activation of phospholipase C as well as Ca2+ mobilization presumably promoted by inositol-1,4,5-trisphosphate was less affected by SIN-1 treatment. In the present study, the effects of SIN-1 on Ca2+ influx have been investigated in more detail using platelets loaded with millimolar concentrations of quin-2. Under these conditions, Ca2+ entry from the medium into the platelet cytoplasm could be followed either by detecting fluorescence quenching by Mn2+ or by determination of 45Ca2+ uptake. Both events were inhibited by SIN-1 in a dose-dependent manner. Furthermore, the inhibition of 45Ca2+ uptake and of fluorescence increase observed in the presence of extracellular Ca2+ displayed remarkably parallel dose-response curves, suggesting that elevation of cyclic GMP brought about by SIN-1 inhibits the opening of "receptor-operated channels" whose precise nature remains to be determined.
J Cardiovasc Pharmacol 1989
PMID:Inhibition of calcium influx in thrombin-stimulated platelets by SIN-1, an activator of soluble guanylate cyclase. 248 86

We have shown previously that in liver, endothelin (ET) binding to plasma membranes causes a rise in cytosolic calcium and activation of glycogenolysis. Here we show that the calcium extrusion pump in liver plasma membranes is inhibited by ET peptides, with ET-1 > or = ET-3 = sarafotoxin S6C-inhibition of the system being potentiated by GTP gamma S. Also, ET-1 stimulates PIP2 hydrolysis in liver plasma membranes in a guanine nucleotide-dependent manner, with ET-1 > or = ET-3 = sarafotoxin S6C. In order to determine the nature of G protein(s) coupling of the ETB receptor to both effectors, antibodies against the C-terminus of different G-protein alpha-subunits were used. Antibodies reactive with Gs alpha blocked ET-1 inhibition of the calcium pump, but they had no effect on ET-1 stimulation of PIP2 hydrolysis. Antibodies reactive with Gq alpha dose-dependently antagonized stimulation of PIP2 breakdown by ET-1 without affecting ET-1 inhibition of the calcium pump. Antibodies reactive with Gi1 alpha/Gi2 alpha had no effect on both systems. We conclude that the calcium signal induced by endothelins in hepatocytes may be consequent to both an activation of phospholipase C and inhibition of the calcium pump, both effectors being coupled to the ETB receptor by different G proteins, Gq and Gs, respectively.
J Cardiovasc Pharmacol 1993
PMID:Endothelin inhibits the calcium pump and stimulates phosphoinositide phospholipase C in liver plasma membranes via two different G proteins, Gs and Gq. 750 31

Parathyroid hypertensive factor (PHF) has been purified from two sources of material: plasma of spontaneously hypertensive rats (SHRs) and culture medium from organ culture of SHR parathyroid glands. Chromatographic characteristics of PHF from these two sources are identical. Biological activity of PHF (assayed as the characteristic delayed hypertensive response in normotensive rats) is sensitive to degradation by treatment in base, and the enzymes trypsin, chymotrypsin, phospholipase C, and phospholipase D. PHF activity may also be extracted from source material with chloroform: methanol (4:1). A hypothetical structure for the active component of PHF is suggested. This is comprised of a peptide liked to a lysophospholipid.
J Cardiovasc Pharmacol 1994
PMID:Purification and structural characterization of parathyroid hypertensive factor. 751 47

Effects of protein kinase C (PKC) activator and inhibitors on adrenal catecholamine release were examined in anesthetized dogs. Output of epinephrine (EPI) and norepinephrine (NE) was determined from adrenal venous blood by high-performance liquid chromatography (HPLC) with electrochemical detection. All drugs were infused intraarterially (i.a.) into the adrenal gland through the phrenic abdominal artery. Infusion of the PKC activator phorbol-12,13-dibutyrate (PDB 0.1 micrograms/min) increased EPI and NE output during basal state and enhanced increases in catecholamine output induced by splanchnic nerve stimulation (SNS 1 and 3 Hz). These effects of PDB were abolished by the PKC inhibitor staurosporine (SSP 0.3 microgram/min), when both drugs were infused simultaneously. Infusion of SSP (0.1, 0.3, and 1 micrograms/min) caused a dose-dependent inhibition of the SNS-induced increases in EPI and NE output. SNS-induced increases in catecholamine output were also inhibited by another PKC inhibitor polymyxin B (PMB 0.1, 0.3, and 1 micrograms/min) and by the phospholipase C (PLC) inhibitor neomycin (NM 0.3, 1, and 3 mg/min). SSP, PMB, and NM did not affect basal output of EPI and NE. These results suggest that activation of PKC promotes release of adrenal catecholamines and provide indirect evidence that activation of PKC and PLC may be involved in SNS-induced release of catecholamines from dog adrenal gland.
J Cardiovasc Pharmacol 1994 Jul
PMID:Effects of protein kinase C activator and inhibitor on adrenal catecholamine release in response to splanchnic nerve stimulation in anesthetized dogs. 752 85


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