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)

Endothelin (ET)-1 is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca(2+) in the myocardium. The object of this study was to examine 1) the influence of ET(A) and ET(B) receptor subtypes, and 2) the role of the phospholipase C (PLC) pathway in mediating ET-1-induced contraction. Left ventricular cardiomyocytes were isolated from the hearts of New Zealand White rabbits (2-2.5 kg) by the use of Langendorff perfusion with collagenase. Cardiomyocyte function was examined during unloaded, electrically stimulated (0.5 Hz) contractions with a video-edge detection system. ET-1 increased cell shortening with greater potency than ET-3: mean EC(50) values were 1.1 x 10(-11) and 2.6 x 10(-10) M, respectively. With the same order of potency, ET-1 and ET-3 increased (P <.05) velocity of cell shortening. The ET(A) receptor-selective antagonist ABT-627 shifted the ET-1-induced cell shortening response curve to the right with a pA(2) value of 10.3. The ET(B) receptor-selective antagonist A-192621 (10(-8)-10(-7) M) did not alter the concentration-response of ET-1. Moreover, the ET(B) receptor-selective agonist sarafotoxin 6c did not have any effect on cell shortening over the concentration range of 10(-11) to 10(-7) M. ET-1 in the presence of the PLC inhibitor U-73122 did not alter the contractile amplitude. However, ET-1 in the presence of the protein kinase C inhibitor bisindolylmalemide increased cell shortening. These findings indicate that 1) the ET(A) receptor subtype, and not the ET(B) receptor subtype, mediates the positive inotropic effect of ET-1, and 2) the response of ET-1 is mediated by a PLC pathway, but not through protein kinase C, in ventricular cardiomyocytes isolated from rabbit myocardium.
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PMID:Endothelin(A) receptor subtype mediates endothelin-induced contractility in left ventricular cardiomyocytes isolated from rabbit myocardium. 1094 58

Immortalized rat Schwann cells (iSC) express endothelin (ET) receptors coupled to inhibition of adenylyl cyclase and stimulation of phospholipase C (PLC). These effects precede phenotypic changes and increased DNA synthesis. We have investigated the role of ETs in the regulation of arachidonic acid (AA) release and mitogen-activated protein kinases (MAPKs). Both ET-1 and ET-3 increased AA release in iSC. This effect was sensitive to the phospholipase A(2) (PLA(2)) inhibitors E:-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H:-pyran-2-one and arachidonyl-trifluoromethyl ketone but was insensitive to inhibitors of PLC or phospholipase D-dependent diacylglycerol generation. ET-1-dependent AA release was also unaffected by removal of extracellular Ca(2+) and blocking the concomitant elevation in [Ca(2+)](i), consistent with participation of a Ca(2+)-independent PLA(2). Treatment of iSC with ETs also resulted in activation of extracellular signal-regulated kinase, c-Jun-NH(2)-terminal kinase (JNK), and p38 MAPK. A cause-effect relationship between agonist-dependent AA release and stimulation of MAPKs, but not the opposite, was suggested by activation of JNK by exogenous AA and by the observation that inhibition of MAPK kinase or p38 MAPK was inconsequential to ET-1-induced AA release. Similar effects of ETs on AA release and MAPK activity were observed in cultures expanded from primary SC and in iSC. Regulation of these effectors may mediate the control of proliferation and differentiation of SC by ETs during peripheral nerve development and regeneration.
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PMID:Endothelins regulate arachidonic acid release and mitogen-activated protein kinase activity in Schwann cells. 1108 Jan 83

A reduction of blood flow in the spiral modiolar artery (SMA), which supplies the cochlea, is implicated in hearing loss and tinnitus. Endothelins are known to be the most potent endogenous vasoconstrictors. The purpose of the present study was to determine whether the SMA responds to endothelin, which receptor type is present and which signal transduction pathway is involved. The SMA was isolated from the gerbil cochlea by microdissection and superfused in a bath chamber on the stage of an inverted microscope. The vascular diameter was measured by video microscopy, and the cytosolic Ca2+ concentration was monitored simultaneously by fluo-4 fluorescence microscopy. ET-1 and ET-3 caused a dose-dependent vasoconstriction with ET-1 being the more potent agonist. The agonist sarafotoxin S6c had no significant effect. The preferential ET(A) receptor antagonist BQ123 had a higher affinity inhibiting the ET-1-induced vasoconstriction than the preferential ET(B) receptor antagonist BQ788. The ET-1-induced vasoconstriction was prevented by inhibition of phospholipase C with U73122. Blockade of the inositol 1,4,5-trisphosphate (IP3) receptor on the sarcoplasmic reticulum Ca2+ stores with 2-aminoethoxydiphenyl borate and depletion of Ca2+ stores by inhibition of the sarcoplasmic Ca2+-ATPase with thapsigargin prevented ET-1-induced cytosolic Ca2+ increase and reduced the ET-1-induced vasoconstriction. These results demonstrate that endothelin causes a vasoconstriction of the SMA, which is mediated via ET(A) receptors. The data suggest that the signal transduction pathway of the ET(A) receptor involves phospholipase C, IP3 receptors and release of Ca2+ from thapsigargin-sensitive Ca2+ stores.
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PMID:ETA receptors in the gerbil spiral modiolar artery. 1188 62

We assessed the possible link between endothelin receptor mediated phosphoinositide breakdown and NO/cGMP signaling pathways in rat arcuate nucleus-median eminence fragments (AN-ME), brain structures known to contain a rich plexus of nitric oxide synthase (NOS)-containing neurons and fibers, together with densely arranged endothelin ETB-receptors-like immunoreactive fibres. Our data show that ET-1, ET-3 and the ETB-receptors agonist, IRL 1620, increased inositol monophosphate (InsP1) accumulation, NOS activity and cGMP formation, in a similar degree. The stimulatory effect of ETs on InsP1 accumulation and cGMP formation was inhibited by the phospholipase C (PLC) inhibitor, neomycin, and the absence of extracellular calcium, suggesting that calcium is involved in endothelin receptor-induced PLC activation. The L-arginine analog, L-NAME, inhibited ET-1 or IRL1620-stimulated cGMP formation. The ETA receptor antagonists BQ 123, did not alter, while the ETB receptor antagonists BQ788 inhibited ETs-induced increase in the PI metabolism, NOS activity and cGMP generation. Our data indicate that in AN-ME, ETB receptor signals through receptor-mediated calcium dependent-stimulation of phosphoinositide breakdown and activation of NOS/cGMP signaling pathway.
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PMID:Multiple signaling pathways involved in the effect of endothelin type B receptor in rat median eminence. 1758 4

We previously reported that endothelins (ETs) are involved in the rat central and peripheral regulation of bile secretion. In this study we sought to establish whether ET-1 and ET-3 modulated submandibular gland secretion when locally or centrally applied. Animals were prepared with gland duct cannulation to collect saliva samples and jugular cannulation to administer sialogogues. ETs were given either into the submandibular gland or brain lateral ventricle. Intraglandularly administered ETs failed to elicit salivation per se. However, ET-1, but not ET-3, potentiated both cholinergic- and adrenergic-evoked salivation through ET(A) receptors. ET-1 decreased cAMP content but increased phosphoinositide hydrolysis, whereas ET-3 attenuated both intracellular pathways. The expression of ET(A) and ET(B) receptor mRNAs as well as that of ETs was revealed in the submandibular gland by RT-PCR. Immunohistochemical studies showed that ET(A) receptor staining was localized around the interlobular ducts and acini, compatible with the myoepithelial cells' location, whereas ET(B) receptor staining was restricted to small blood vessels. When applied to the brain, both ETs induced no salivation but enhanced cholinergic- and adrenergic-evoked salivary secretion through parasympathetic pathways. ET-1 response was mediated by brain ET(A) receptors, whereas that of ET-3 was presumably through nonconventional ET receptors. Present findings show that ETs are involved in the brain regulation of cholinergic- and adrenergic-stimulated submandibular gland secretion through the activation of distinct brain ET receptors and parasympathetic pathways. However, when ETs were administered into the gland, only ET-1 enhanced cholinergic and adrenergic salivation likely through myopithelial cell contraction by activating ET(A) receptors coupled to phospholipase C. The presence of ETs and ET receptors suggests the existence of an endothelinergic system in the submandibular gland.
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PMID:Endothelins participate in the central and peripheral regulation of submandibular gland secretion in the rat. 2094 54

Endothelins (ETs) are widely expressed in the olfactory bulb (OB) and other brain areas where they function as neuropeptides. In a previous study we reported that in the OB ET-1 and ET-3 participate in the long-term regulation of tyrosine hydroxylase (TH), the key enzyme in catecholamine biosynthesis. ETs stimulate TH activity by increasing total and phosphorylated enzyme levels as well as its mRNA. ET-1 response is mediated by a super high affinity ETA receptor coupled to adenylyl cyclase/protein kinase A and Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II) activation whereas that of ET-3 through an atypical receptor coupled not only to these signaling pathways but also to phospholipase C (PLC)/protein kinase C pathway. Given the participation of PLC and CaMKII in the regulation of TH by ETs in the OB we sought to establish the contribution of calcium to ETs response. Present findings show that calcium released from ryanodine-sensitive channels and extracellular calcium were necessary to stimulate TH by ETs through CaMK-II. On the other hand, intracellular calcium released by the endoplasmic reticulum partially mediated ETs-evoked increase in TH mRNA but calcium influx and CaMK-II inhibition abolished the response. However calcium mechanisms were not involved in ETs-evoked increase in TH protein content. Present findings support that different sources of calcium contribute to the long-term modulation of TH activity and expression mediated by ETs in the rat OB.
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PMID:Calcium-dependent mechanisms involved in the modulation of tyrosine hydroxylase by endothelins in the olfactory bulb of normotensive rats. 2335 75


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