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)

Proteinase-activated receptors (PARs1-4) have recently been identified as the molecular entity underlying the cellular effects of serine proteinases. In the present study we have investigated PAR2 signalling, expression and desensitization using cultured and acute slice preparations. Trypsin, SLIGRL and 2f-LIGKV-OH, agonists for PAR2, induced a transient increase in intracellular Ca(2+) levels in both neurons and astrocytes, via activation of the phospholipase C/IP(3) pathway. Furthermore, a single application of trypsin, but not SLIGRL nor 2f-LIGKV-OH, leads to prolonged desensitization of PAR2 responses. PAR2 immunoreactivity was observed in neurons (glutamatergic and GABAergic) and astrocytes within cultures and acute slices, with prominent labelling in neuronal somata and proximal dendrites. Functionally, cultured neurons which exhibited the highest levels of PAR2 labelling, also exhibited the largest Ca(2+) signals upon PAR2 activation. Given the importance of Ca(2+) signalling in hippocampal synaptic plasticity and neurodegeneration, PAR2 may play a key modulatory role in these processes.
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PMID:Characterization of proteinase-activated receptor 2 signalling and expression in rat hippocampal neurons and astrocytes. 1643 Sep 28

We tested the hypothesis that the serine protease trypsin can indirectly activate the epithelial Na(+) channel (ENaC). Experiments were carried out in Xenopus oocytes and examined the effects on the channel formed by all three human ENaC subunits and that formed by Xenopus epsilon and human beta and gamma subunits (epsilonbetagammaENaC). Low levels of trypsin (1-10 ng/ml) were without effects on the oocyte endogenous conductances and were specifically used to test the effects on ENaC. Addition of 1 ng/ml trypsin for 60 min stimulated the amiloride-sensitive human ENaC conductance (g(Na)) by approximately 6-fold. This effect on the g(Na) was [Na(+)]-independent, thereby ruling out an interaction with channel feedback inhibition by Na(+). The indirect nature of this activation was confirmed in cell-attached patch clamp experiments with trypsin added to the outside of the pipette. Trypsin was comparatively ineffective at activating epsilonbetagammaENaC, a channel that exhibited a high spontaneous open probability. These observations, in combination with surface binding experiments, indicated that trypsin indirectly activated membrane-resident channels. Activation by trypsin was also dependent on catalytic activity of this protease but was not accompanied by channel subunit proteolysis. Channel activation was dependent on downstream activation of G-proteins and was blocked by G-protein inhibition by injection of guanyl-5'-yl thiophosphate and by pre-stimulation of phospholipase C. These data indicate a receptor-mediated activation of ENaC by trypsin. This trypsin-activated receptor is distinct from that of protease-activated receptor-2, because the response to trypsin was unaffected by protease-activated receptor-2 overexpression or knockdown.
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PMID:Indirect activation of the epithelial Na+ channel by trypsin. 1762 47

The effect of trypsin on vascular tone and the cytosolic calcium concentration ([Ca(2+)](i)) of endothelial and smooth muscle cells were examined in the rat aorta. A calcium indicator, fura-PE3, was used to measure [Ca(2+)](i) simultaneously with vascular tone. In the endothelium-intact rat aorta, carbachol and trypsin increased [Ca(2+)](i) in a dose-dependent manner. In the endothelium-denuded rat aorta, carbachol did not change [Ca(2+)](i), but trypsin slightly increased it. Addition of trypsin to the norepinephrine-stimulated rat aorta relaxed the muscle with an additional increase in [Ca(2+)](i). Under calcium-free conditions, trypsin induced a transient increase in [Ca(2+)](i). Trypsin-induced endothelium-dependent relaxation was inhibited by preincubation with l-NMMA, an endothelial NO synthase inhibitor, U-73122, a phospholipase C inhibitor, cyclopiazonic acid, a sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase blocker, and lanthanum, a nonselective Ca(2+) channel blocker. However, indomethacin, a nonselective cyclooxygenase inhibitor, and SKF-96365, a store-operated Ca(2+)-channel blocker, had no effect on the trypsin-induced relaxation. These results suggest that trypsin increases [Ca(2+)](i) in the endothelial cells through SKF-96365-insensitive Ca(2+) channels and regulates the release of NO, which results in relaxation of the rat aorta.
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PMID:Effects of trypsin on cytosolic calcium levels in the rat aortic endothelium. 2147 94


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