Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin (ET) and GnRH act through specific receptors to promote Ca2+ mobilization and influx pathways in pituitary gonadotrophs. In the present study cytoplasmic calcium ([Ca2+]i) and secretory responses to these two agonists are compared. In single gonadotrophs, low concentrations of both agonists cause oscillatory [Ca2+]i responses after a latent period. Such responses usually consist of discrete transients arising from the normal resting level, but are sometimes super-imposed on an elevated basal calcium level. At high doses, ET-1 and GnRH induce biphasic responses, composed of a spike phase followed by a plateau that often shows high frequency and low amplitude Ca2+ transients. The duration of the latent period and the frequency of the subsequent oscillations are correlated, and both are dependent on agonist concentration. The frequencies and amplitudes of Ca2+ spiking are also interrelated; increases in frequency are followed by more rapid decreases in the amplitude of the Ca2+ transients. After K(+)-induced depolarization, gonadotrophs retain their oscillatory Ca2+ responses to ET-1 and GnRH, with the same frequency as controls. Activation of protein kinase-C by phorbol esters does not alter the frequency of ET-induced Ca2+ transients, but significantly reduces their amplitudes. In contrast, treatment with nanomolar concentrations of thapsigargin converts ET-induced oscillations into a biphasic response, suggesting that Ca(2+)-ATPase in the endoplasmic reticulum participates in the oscillatory mechanism. The two agonists differ in their threshold doses and concentration dependence, ET being significantly less potent than GnRH. Also, gonadotrophs stimulated by ET-1 exhibit different post-treatment responsiveness than those exposed to GnRH. While GnRH-treated cells recover their full [Ca2+]i and secretory responses within 30 min as well as normal [Ca2+]i and secretory responses to ET-1, endothelin-treated cells are refractory to further stimulation with ET and exhibit either attenuated or enhanced Ca2+ and LH responses to GnRH, depending on the duration of exposure to ET-1 and the subsequent recovery period. These data indicate that both receptors use the same mechanism(s) for Ca2+ release, but have different capacities to generate, maintain, and reinitiate the Ca2+ signal.
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PMID:Differential actions of endothelin and gonadotropin-releasing hormone in pituitary gonadotrophs. 144 20

We recently found that TGF-beta increases ET-1 secretion in MDCK, a renal tubular cell line. The secretion of ET-1, by a confluent monolayer of MDCK cells grown on a filter, to the basolateral side of the epithelium was two times greater than that to the apical side. However, TGF-beta-increased ET-1 and big ET-1 secretion were exclusively released to the basolateral side. We investigated the mechanism of polarized secretion of ET-1 and big ET-1 in MDCK cells. After 24 h of incubation with 80 pM TGF-beta, basolateral secretion of both ET-1 and big ET-1 increased two to threefold without a significant increase on the apical side. TGF-beta-stimulated ET-1 and big ET-1 secretion in the basolateral bath were inhibited when 10 microM amiloride (Na+ channel blocker) or 1 microM ouabain (Na+, K(+)-ATPase inhibitor) was added for 3 h. Polarized secretion of ET-1 and big ET-1 was not affected. In contrast, 10 mM NH4Cl or 0.2 mM chloroquine (both lysosomal function inhibitors) reduced TGF-beta-stimulated ET-1 secretion in the basolateral bath whereas big ET-1 secretion in the apical bath increased two times. Thus, the polarity of big ET-1 secretion was reversed. In addition, the conversion rate from big ET-1 to ET-1 was significantly decreased from 80 to 55% by inhibiting lysosomal function. Prepro-ET-1 mRNAs 3 h after these perturbations were virtually unaltered. Our data show that ET-1 and big ET-1 secretion may be regulated by cell Na+ flux and that lysosomal functions may play some roles in the conversion of big ET-1 to mature ET-1 and in polarized secretion of big ET-1. Translational or posttranslational regulation may play an additional role in ET-1 secretion as well as the mRNA level.
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PMID:Polarized secretion of endothelin-1 and big ET-1 in MDCK cells is inhibited by cell Na+ flux and disrupted by NH4Cl. 172 40

In anesthetized Sprague-Dawley rats, cerebrolateral ventricular administration of potassium chloride solutions (KCl, 0.375-1.25 mumol, i.c.v.) produced concentration-dependent reductions in the arterial blood pressure and heart rate. These responses were significantly attenuated by prior i.c.v.-administration ouabain, a selective inhibitor of the Na+ pump, and by endothelin (ET-1), an endogenous peptide that is present in the CNS, suggesting that this peptide may participate in the neural regulation of arterial pressure via modulation of Na(+)-pump activity. Although both acute fluid volume expansion and/or osmotic stimulus have been shown to facilitate the release of the endogenous Na(+)-pump inhibitor(s) into the circulation, only volume expansion significantly attenuated the cardiovascular effects of i.c.v. potassium chloride. These observations collectively suggest that the Na+, K(+)-ATPase activity in CNS and Na(+)-pump inhibitors may play a significant role in the central regulation of arterial pressure under certain physiological conditions.
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PMID:Physiological significance of Na+/K(+)-ATPase activity in the central nervous system and endogenous sodium-pump inhibitors in the neural regulation of arterial blood pressure. 750 16

The effect of endothelins (ET-1 and ET-3) on 86Rb+ uptake as a measure of K+ uptake was investigated in cultured rat brain capillary endothelium. ET-1 or ET-3 dose-dependently enhanced K+ uptake (EC50 = 0.60 +/- 0.15 and 21.5 +/- 4.1 nM, respectively), which was inhibited by the selective ETA receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ETB agonists IRL 1620 [N-succinyl-(Glu9,-Ala11,15)-ET-1] and sarafotoxin S6c, nor the ETB receptor antagonist IRL 1038 [(Cys11,Cys15)-ET-1] had any effect on K+ uptake. Ouabain (inhibitor of Na+,K(+)-ATPase) and bumetanide (inhibitor of Na(+)-K(+)-Cl- cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K+ uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na+,K(+)-ATPase and Na(+)-K(+)-Cl- cotransport. ET-1- but not PMA-stimulated K+ uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na+/H+ exchange system), suggesting a linkage of Na+/H+ exchange with ET-1-stimulated Na+,K(+)-ATPase and Na(+)-K(+)-Cl- cotransport activity that is not mediated by PKC.
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PMID:Endothelin 1 stimulates Na+,K(+)-ATPase and Na(+)-K(+)-Cl- cotransport through ETA receptors and protein kinase C-dependent pathway in cerebral capillary endothelium. 756 53

Endothelin (ET) potently inhibits arginine vasopressin (AVP)-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and Na-K-adenosinetriphosphatase (Na-K-ATPase) activity in the inner medullary collecting duct (IMCD). At least two types of ET receptors exist: ETA [binds ET-1 > ET-3 = sarafotoxin S6c (S6c)] and ETB (binds ET-1 = ET-3 = S6c). We examined which of these receptors mediates biological actions of ET in freshly isolated rat IMCD cells. Binding studies revealed comparable displacement of 125I-ET-3 by ET-1, ET-3, and S6c, whereas 125I-ET-1 was displaced by ET-1 >> ET-3 = S6c. Together, these studies confirm the presence of receptors in the IMCD with ETA and ETB binding characteristics. ET-1, ET-3, and S6c were equipotent in reducing AVP-stimulated cAMP accumulation. BQ-123, at concentrations selective for ETA receptor antagonism, did not alter the effect of ET-1, ET-3, or S6c. Pertussis toxin or protein kinase C blockade, but not indomethacin, inhibited the effect of ET-1 and S6c on AVP-stimulated cAMP accumulation, consistent with activation of the same signal transduction pathways. ET-1 and S6c were equipotent in reducing forskolin-stimulated cAMP accumulation, ruling out inhibition of AVP-receptor interaction as a common mechanism of action. Finally, ET-1, ET-3, and S6c caused comparable stimulation of prostaglandin E2 (PGE2) accumulation, an effect that was not blocked by BQ-123. These data indicate that an ETB-like receptor mediates ET stimulation of PGE2 and inhibition of AVP-enhanced cAMP accumulation in the IMCD. The function of the ETA-like receptor in the IMCD remains to be determined.
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PMID:Endothelin B receptor mediates ET-1 effects on cAMP and PGE2 accumulation in rat IMCD. 769 6

The mechanism of Ca++ mobilization induced by endothelins (ETs) and the receptor subtype responsible for this effect were examined in the endothelium of rabbit aortic valve. In the endothelium loaded with fura-2, ET-1 (1-100 nM) induced large transient increase followed by small sustained increase in cytosolic Ca++ level ([Ca++]i) in a concentration-dependent manner. ET-3 induced only a small increase in [Ca++]i at higher concentrations (100-300 nM) than ET-1, whereas a selective ETB agonist, 100 nM IRL 1620 (succinyl-[Glu9, Ala11,15]ET-1 8-21), was ineffective. A selective ETA antagonist, 3 microM BQ-123, (cyclo [-Asp-Pro-Val-Leu-Trp-]) but not a selective ETB antagonist, 10 microM RES-701-1 [cyclic (Gly1-Asp9) (Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp- Trp-Phe-Phe-Asn-Tyr-Tyr-Trp)], inhibited the effects of ET-1 and ET-3. The sustained increase in [Ca++]i induced by ET-1 was abolished by 30 microM La , although 100 nM nicardipine was ineffective. In the absence of external Ca++ (with 0.5 mM EGTA), ET-1 induced only a transient increase in [Ca++]i, which was inhibited by an inhibitor of Ca+(+)-ATPase in endoplasmic reticulum, 1 microM thapsigargin. However, an inhibitor and an activator of Ca+(+)-induced Ca+(+)-release channel, 10 microM ryanodine and 10 mM caffeine, did not change [Ca++]i. These results suggest that, in the endothelium of rabbit aortic valve, only the ETA receptor mediates the effects of ETs to increase [Ca++]i, which is attributable to the release of Ca++ from thapsigargin-sensitive and ryanodine-insensitive Ca++ stores and also to the Ca++ influx through La (-)sensitive and dihydropyridine-insensitive Ca++ channels.
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PMID:Ca++ mobilization mediated by endothelin ETA receptor in endothelium of rabbit aortic valve. 799 47

We examined the effects of tetrandrine (TET) on Ca2+ mobilization in various types of cells using inositol trisphosphate-generating drugs and compared it with those using the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG) which is a tool for analyzing Ca2+ store-regulated Ca2+ entry (capacitative Ca2+ entry). In rat pheochromocytoma PC12 cells, 100 microM TET abolished high K+ (30 mM)-induced sustained increase in [Ca2+]i and partially inhibited bradykinin (1 microM)-induced or TG (100 nM)-induced Ca2+ entry. In NIH/3T3 fibroblasts, 100 microM TET abolished Ca2+ entry induced by bombesin (1 microM) or TG (100 nM). In rat glioma C6 cells, the addition of 100 microM TET reduced the sustained elevation of [Ca2+]i induced by endothelin 1 (10 nM) or TG (100 nM) declining to the resting level. In rat parotid acinar cells, 100 microM TET abolished a sustained increase in [Ca2+]i induced by carbachol (100 microM) or TG (100 nM). In human leukemia T-cell line Jurkat, 100 microM TET did not inhibit Ca2+ entry evoked by the anti-CD3 antibody OKT3 (10 micrograms/ml) or TG (100 nM). The present results suggest that the action of TET on Ca2+ entry is dependent on cell types.
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PMID:Calcium antagonistic actions of tetrandrine depend on cell types. 858 49

The preproendothelin-1 (preproET-1) gene is induced by thrombin after phosphorylation of nonreceptor protein tyrosine kinase pathways. This study investigated the contribution of Ca2+/calmodulin-dependent intracellular signaling cascades to this pathway and measured ET-1 mRNA levels by Northern blot analysis in human endothelial cells. Increased intracellular Ca2+ levels in response to Ca2+ ionophore or Ca2+ ATPase inhibitors tert-butylhydroquinone and thapsigargin mimicked thrombin actions on ET-1 mRNA induction. Thrombin-mediated activation of ET-1 mRNA was reduced by specific calmodulin antagonists W7 or calmidazolium and after inhibition of CaM kinase II by KN-62. Inhibition of calcium/calmodulin-dependent phosphatase calcineurin by cyclosporin A, however, stimulated ET-1 mRNA in human endothelial cells. Phosphotyrosine immunoblot assays show that calcium/calmodulin-dependent signaling pathways precede thrombin-induced tyrosine phosphorylation, and that the calcium/calmodulin-dependent phosphatase calcineurin also exerts its effects via activation of protein tyrosine kinases. These observations demonstrate that thrombin stimulates the preproET-1 gene in human endothelial cells through calcium-dependent activation of CaM kinase and protein tyrosine kinases, and that calcineurin may also participate in regulation of the prepro ET-1 gene.
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PMID:Thrombin-mediated ET-1 gene regulation involves CaM kinases and calcineurin in human endothelial cells. 858 30

1. We investigated the characteristics of endothelin (ET)-induced contraction and changes in intracellular Ca2+ concentration ([Ca2+]i) using the fura-2-loaded and non-loaded rabbit iris dilator. ET-1 and ET-2 (3-100 nM) and ET-3 (30-100 nM) caused contraction in a concentration-dependent fashion. 2. The selective ETB-receptor agonists, IRL1620 and sarafotoxin S6c produced only a small contraction or no contraction at a concentration of 1 microM. The rank order of potencies for the contraction (pD2 value) was ET-1 = ET-2 > ET-3 >> sarafotoxin S6c = IRL1620. 3. The contractile response to ET-3 was antagonized by pretreatment with BQ-123 (10 nM), a selective ETA receptor antagonist. The contractile responses to ET-1 and ET-2 were antagonized by pretreatment with BQ-123 (10 microM), but not at a concentration of 10 nM. 4. ETs increased [Ca2+]i and sustained muscle contraction. ET-1 (100 nM), ET-2 (100 nM), and ET-3 (1 microM) induced an elevation of [Ca2+]i consisting of two components: first a rapid and transient elevation to reach a peak, followed by a second, sustained elevation; a sustained contraction was produced without a transient contraction. The ETB receptor-selective agonist, IRL1620 (1 microM) and sarafotoxin S6c (1 microM) also induced a rapid and transient elevation of [Ca2+]i to reach a peak and a sustained elevation, together with only a small contraction or no contraction. 5. ET-1 (100 nM) induced a transient increase in [Ca2+]i in a Ca(2+)-free, 2 mM EGTA-containing physiological saline solution (Ca(2+)-free PSS), and a small sustained contraction which was significantly different from that induced by ET-1 (100 nM) in normal PSS. The ET-1-induced increase in [Ca2+]i and sustained contraction were not affected by the voltage-dependent Ca2+ channel blocker, nicardipine (10 microM). The ET-1-induced transient increase in [Ca2+]i was significantly reduced by the sarcoplasmic reticulum (SR) Ca(2+)-ATPase inhibitor, cyclopiazonic acid (30 microM); however, the ET-1-induced sustained contraction was not affected by this agent. 6. The selective ETA receptor antagonist, BQ-123 (100 nM) reduced the ET-3 (100 nM)-induced contraction, but did not affect the transient increase or elevation of the second phase of [Ca2+]i. However, this antagonist at 1 microM did not affect the ET-1 (100 nM)- and ET-2 (100 nM)-induced elevation of [Ca2+]i and contractile response, or the IRL1620-induced elevation of [Ca2+]i. 7. The selective ETB receptor antagonist, BQ-788 (1 microM) reduced the transient increase in [Ca2+]i induced by ET-1 (30 nM), ET-2 (30 nM), ET-3 (100 nM) and IRL1620 (1 microM), but did not affect the sustained elevation of [Ca2+]i and contractile responses produced by ET-1, ET-2 and ET-3. 8. Pretreatment with IRL1620 (1 microM) reduced the increase in [Ca2+]i induced by IRL1620 (1 microM) and sarafotoxin S6c (1 microM), as well as the ET-1 (100 nM)-, ET-2 (100 nM)- and ET-3 (1 microM)-induced elevation of [Ca2+]i, whereas in the presence of IRL1620, ET-1-, ET-2- and ET-3-induced contractions were unaltered. 9. These results suggest that ETA and ETB receptor subtypes exist in the rabbit iris dilator muscle, and that the ETA receptor is divided into: (1) BQ-123-sensitive ETA subtypes activated by ET-1, ET-2 and ET-3, and (2) BQ-123-insensitive ETA subtypes activated by ET-1 and ET-2, which cause the sustained increase of [Ca2+]i and contraction; in contrast, ETB receptor subtypes are activated by ET-1, ET-2, ET-3, IRL1620 and sarafotoxin S6c and cause the transient and sustained increase in [Ca2+]i which is not able to contract the smooth muscle.
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PMID:Characterization of endothelin receptor subtypes mediating Ca2+ mobilization and contractile response in rabbit iris dilator muscle. 888 26

The role of Na+/K+ ATPase in vascular relaxation has been studied by determining its inhibitory effects on 2-mm segments from rabbit central ear and femoral arteries, mounted for isometric tension recording. Acetylcholine (10(-8)-10(-4) M), the nitric oxide donor sodium nitroprusside (10(-8)-3 x 10(-4) M), the potassium channel agonist cromakalim (10(-8) x 10(-5) M), histamine (10(-8)-10(-4) M) in the presence of the H1 antagonist chlorpheniramine (10(-5) M), and papaverine (10(-6)-3 x 10(-4) M) all produced arterial relaxation in ear and femoral arteries precontracted with endothelin 1. Addition of potassium (6 x 10(-3)-1.2 x 10(-2) M) caused relaxation of the same arteries preincubated in potassium-free medium. Ouabain (10(-5) M) an inhibitor of Na+/K+ ATPase, reduced the relaxation of ear arteries, but not of femoral arteries, in response to acetylcholine; it also reduced the response to sodium nitroprusside, cromakalim or histamine, and abolished the relaxation to potassium, but did not modify the response to papaverine, in both types of artery. These results suggest that Na+/K+ ATPase might play a role in the relaxation of ear and femoral arteries to nitrovasodilators, to potassium channel openers and to activation of histamine receptors, and that Na+/K+ ATPase might play a role in the cholinergic relaxation of ear, but not femoral arteries, suggesting that the mechanism of cholinergic relaxation might differ in each type of artery.
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PMID:Role of Na+/K+ ATPase on the relaxation of rabbit ear and femoral arteries. 895 8


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