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)

Dantrolene is felt to inhibit the release of Ca2+ from vesicular stores but only in response to certain stimuli; the mechanism responsible for its effects is unclear. Since our recent studies implicated arachidonic acid and other polyunsaturated fatty acids in Ca2+ mobilization and insulin release from pancreatic islets, we have now examined the effect of dantrolene on fatty acid-induced 45Ca2+ efflux and insulin release. Dantrolene inhibited insulin secretion induced by exogenous unsaturated fatty acids as well as that caused by endogenous fatty acids (generated via the exogenous provision of pancreatic phospholipase A2, or by p-hydroxymercuribenzoic acid, which prevents the reacylation of free fatty acids). In contrast, the effects of 50 mM K+, 2 mM BaCl2, 1 mM isobutylmethylxanthine or lysophosphatidylcholine were not impaired, suggesting that dantrolene does not inhibit nonspecifically the influx, mobilization or cellular effects of Ca2+, or poison exocytosis in general. However, dantrolene did reduce insulin secretion triggered by 12-O-tetradecanoylphorbol-13-acetate, mezerein or exogenous phospholipase C, all of which can activate protein kinase C; this inhibition was not accompanied by alterations in 45Ca2+ efflux. Furthermore, the 45Ca2+ efflux induced by phospholipase A2 or p-hydroxymercuribenzoic acid was not reduced by dantrolene. We conclude that the insulin secretion stimulated by unsaturated fatty acids involves two effects (one on Ca2+ fluxes, and one independent of Ca2+ mobilization). Dantrolene, in turn, may selectively probe such fatty acid-dependent insulin release; its inhibitory effect is predominantly, if not totally, independent of effects on Ca2+ fluxes, and may involve the inhibition of the effects of protein kinase C on exocytosis.
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PMID:Dantrolene-induced inhibition of insulin release. A mechanism independent of effects on calcium fluxes. 245 11

Inhibitors of pancreatic islet lipoxygenase (LPX) impair nutrient-induced insulin (I) release. To define the mechanism of action of these inhibitors, studies were carried out at subthreshold glucose concentrations (0-1.7 mM) in order to minimize any effects of LPX blockade on the potentiating effect of extracellular fuels. Barium chloride (Ba2+; 2 mM) increased 45Ca2+ release from prelabeled islets in Ca2+-free medium and, thus, is a model for the mobilization of intracellular Ca2+ stores. Inhibition of LPX (using nordihydroguaiaretic acid, BW755c [3-amino-1-(trifluomethyl-phenyl)2-pyrazoline] or butylated hydroxytoluene) did not have any consistent effect on the influx of Ba2+ (as assessed by 133Ba uptake) or on the consequent release of cellular Ca2+ stores; however, each LPX inhibitor vitiated Ba2+-induced I release. The LPX inhibitors were not merely acting as nonspecific antioxidants, since two inhibitors which do not act by scavenging hydroperoxides (5,8,11,14-eicosatetraynoic acid and 15-hydroxy-5,8,11,13-eicosatetraenoic acid) also impeded the effect of Ba2+ on I secretion; furthermore, a series of hydroxyl radical scavengers, reducing agents, or agents that block nonenzymatic and/or NADPH-activated lipid peroxidation did not inhibit I secretion. LPX inhibitors also blocked the residual I response to 16.7 mM glucose in Ca2+-free medium. Additionally, they reduced secretion induced by 46 mM K+ or 1 mM isobutylmethylxanthine (provided in the presence of extracellular Ca2+), without inhibiting K+- or isobutylmethylxanthine-induced Ca2+ fluxes. Stimuli sensitive to LPX blockade were also antagonized by antimycin A (an inhibitor of energy flux) or TMB-8 [8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride; which appeared to deplete critical intracellular Ca2+ stores]. In contrast, the effects of exogenous phospholipase C (and several other Ca2+-dependent membrane-active agonists) were resistant to the LPX inhibitors, TMB-8, and antimycin A; thus, LPX inhibitors are not nonspecific global poisons of all Ca2+-dependent exocytotic hormone release. We conclude that LPX (or a very similar enzyme) may modulate the effects (or redistribution) of an ATP-dependent trigger pool of Ca2+ at a site distal to and independent of its mobilization by primary islet agonists. LPX inhibitors also blocked secretion induced by 12-O-tetradecanoyl-phorbol-13-acetate; this effect may reflect an effect of LPX on the activation of protein kinase C or a modulation of its synergism with the same trigger Ca2+ pool(s).
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PMID:Lipoxygenase inhibitors reduce insulin secretion without impairing calcium mobilization. 310 21

To study the effects of oxytocin on both spontaneous phasic contractions and K+ outward currents (IK) of the so-called 'non-target' smooth muscle cells, physiological concentrations of oxytocin ranging between 10(-12) mol/l and 10(-8) mol/l were applied to smooth muscle preparations and single voltage-clamped cells isolated from the circular layer of the guinea-pig gastric antrum. Oxytocin (10(-12) mol/l to 10(-8) mol/l) suppressed, in a dose-dependent manner, the tetrodotoxin- and atropine-resistant spontaneous phasic contractions and shifted rightward the dose-response curves of 10(-7) mol/l charybdotoxin and 10(-3) mol/l BaCl2. In cells with preloaded intracellular Ca2+ stores, oxytocin (10(-12) mol/l to 10(-9) mol/l) caused a dose-dependent activation of the charybdotoxin-blockable non-inactivating component of IK (IK(sl)) of single voltage-clamped cells, which was accompanied by hyperpolarization of the cell membranes. 8Lys-vasopressin and 8arg-vasopressin failed to mimic the effects of oxytocin on both contraction and K+ currents. Further, the oxytocin-induced activation of IK(sl) was effectively antagonized by 5 x 10(-8) mol/l U-73122 or 5 x 10(-6) mol/l 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (inhibitors of the cell membrane phospholipase C), as well as by intracellularly applied heparin (selective inhibitor of inositol-1,4,5-trisphosphate (IP3)-induced Ca2+ release channels). In cells incubated in the absence of Ca2+ entry throughout the study, oxytocin (10(-9) mol/l) caused a slight and transient increase of IK(sl) amplitudes. Neither ryanodine (10(-6) mol/l) nor cyclopiazonic acid (10(-6) mol/l) were able to restore the IK-activating effect of oxytocin in these cells. The data obtained suggest (i) that selective oxytocin receptors are present on the membranes of guinea-pig antral smooth muscle cells, (ii) that the oxytocin-related relaxation may result from the activation of Ca(2+)-sensitive K+ conductivity via activation of IP3-induced release of Ca2+ from the submembrane located cisternae of the sarcoplasmic reticulum Ca2+ stores and (iii) in turn, this evokes a non-inactivating component of IK, hyperpolarizing the cell membrane.
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PMID:Oxytocin-induced changes in single cell K+ currents and smooth muscle contraction of guinea-pig gastric antrum. 918 74

Thyrotropin-releasing hormone (TRH) is released in high concentrations into gastric juice, but its direct effect on gastric smooth muscles has not been studied yet. We undertook studies on TRH effect on gastric smooth muscle using contraction and patch clamp methods. TRH was found to inhibit both acetylcholine- and BaCl2-induced contractions of gastric strips. TRH, applied to single cells, inhibited the voltage-dependent Ca2+ currents and activated the whole-cell K+ currents. The TRH-induced changes in K+ currents and membrane potential were effectively abolished by inhibitors of either intracellular Ca2+ release channels or phospholipase C. Neither activators, nor blockers of protein kinase C could affect the action of TRH on K+ currents. In conclusion, TRH activates K+ channels via inositol-1,4,5-trisphosphate-induced release of Ca2+ in the direction to the plasma membrane, which in turn leads to stimulation of the Ca2+-sensitive K+ conductance, membrane hyperpolarization and relaxation. The data imply that TRH may act physiologically as a local modulator of gastric smooth muscle tone.
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PMID:Thyrotropin-releasing hormone activates KCa channels in gastric smooth muscle cells via intracellular Ca2+ release. 1150 21

The pancreatic hormone glucagon hyperpolarizes the liver cell membrane. In the present study, we investigated the cellular signalling pathway of glucagon-induced hyperpolarization of liver cells by using the conventional microelectrode method. The membrane potential was recorded in superficial liver cells of superfused mouse liver slices. In the presence of the K+ channel blockers tetraethylammonium (TEA, 1 mmol/l) and Ba2+ (BaCl2, 5 mmol/l) and the blocker of the Na+/K+ ATPase, ouabain (1 mmol/l), no glucagon-induced hyperpolarization was observed confirming previous findings. The hyperpolarizing effect of glucagon was abolished by the leukotriene B4 receptor antagonist CP 195543 (0.1 mmol/l) and the purinergic receptor antagonist PPADS (5 micromol/l). ATPgammaS (10 micromol/l), a non-hydrolyzable ATP analogue, induced a hyperpolarization of the liver cell membrane similar to glucagon. U 73122 (1 micromol/l), a blocker of phospholipase C, prevented both the glucagon- and ATPgammaS-induced hyperpolarization. These findings suggest that glucagon affects the hepatic membrane potential partly by inducing the formation and release of leukotrienes and release of ATP acting on purinergic receptors of the liver cell membrane.
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PMID:Leukotriene and purinergic receptors are involved in the hyperpolarizing effect of glucagon in liver cells. 1584 96