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)

We have studied the Ca(2+) leak pathways in the endoplasmic reticulum of pancreatic acinar cells by directly measuring Ca(2+) in the endoplasmic reticulum ([Ca(2+)](ER)). Cytosolic Ca(2+) ([Ca(2+)](C)) was clamped to the resting level by a BAPTA-Ca(2+) mixture. Administration of cholecystokinin within the physiological concentration range caused a graded decrease of [Ca(2+)](ER), and the rate of Ca(2+) release generated by 10 pm cholecystokinin is at least 3x as fast as the basal Ca(2+) leak revealed by inhibition of the endoplasmic reticulum Ca(2+)-ATPase. Acetylcholine also evokes a dose-dependent decrease of [Ca(2+)](ER), with an EC(50) of 0.98 +/- 0.06 microm. Inhibition of receptors for inositol 1,4,5-trisphosphate (IP(3)) by heparin or flunarizine blocks the effect of acetylcholine but only partly blocks the effect of cholecystokinin. 8-NH(2) cyclic ADP-ribose (20 microm) inhibits the action of cholecystokinin, but not of acetylcholine(.) The basal Ca(2+) leak from the endoplasmic reticulum is not blocked by antagonists of the IP(3) receptor, the ryanodine receptor, or the receptor for nicotinic acid adenine dinucleotide phosphate. However, treatment with puromycin (0.1-1 mm) to remove nascent polypeptides from ribosomes increases Ca(2+) leak from the endoplasmic reticulum by a mechanism independent of the endoplasmic reticulum Ca(2+) pumps and of the receptors for IP(3) or ryanodine.
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PMID:Basal and physiological Ca(2+) leak from the endoplasmic reticulum of pancreatic acinar cells. Second messenger-activated channels and translocons. 1199 89

In small segments of circular smooth muscle bundle isolated from the guinea-pig gastric antrum, depolarization of the tissue with intracellular current stimuli evoked regenerative slow potentials after a refractory period of 5-10 s. The refractory period changed inversely with the amplitude and duration of the stimulating depolarization. Thapsigargin (an inhibitor of calcium-ATPase at internal stores), 2-aminoethoxydiphenyl borate (2-APB, an inhibitor of inositol 1,4,5-trisphosphate (IP3)-receptor-mediated Ca2+ release), and carbonyl cyanide m-chlorophenyl-hydrazone (a mitochondrial protonophore) reduced the amplitude of slow potentials, with no significant alteration of the refractory period. Bisindolylmaleimide I or chelerythrine (inhibitors of protein kinase C, PKC) increased the refractory period and inhibited the amplitude of slow potentials. These results indicate that the refractory period and amplitude of slow potentials are related to the activation of PKC and the amount of Ca2+ released from the internal stores through activation of IP3 receptors, respectively. Acetylcholine (ACh) reduced the refractory period and increased the amplitude of slow potentials: the former was antagonized by chelerythrine and the latter by 2-APB. The results suggest that ACh has dual actions; stimulation of the metabolism of inositol phosphate and activation of PKC. Phorbol-12-myristate-13-acetate, a selective stimulant of PKC, at low concentrations (< 10 nM) mimicked the actions of ACh and at high concentrations reduced the frequency of slow potentials and increased the refractory period. The possible involvement of the concentration-dependent differences in the actions of phorbol ester on the translocation of PKC was considered.
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PMID:Excitation of smooth muscles isolated from the guinea-pig gastric antrum in response to depolarization. 1218 Dec 88

The role of Na/Ca exchange and intracellular mobilized Ca2+ in modifying the depression of defensive behavior command neuron cholinosensitivity induced by the the Na,K pump inhibitor ouabain was studied in common snails using a cellular analog of habituation. Integral transmembrane acetylcholine-evoked currents (ACh currents) were recorded using a two-electrode membrane potential clamping technique. Decreases in neuron cholinosensitivity in the cellular analog of habituation were assessed in terms of the depth of depression of the amplitude of ACh currents during rhythmic local application of acetylcholine (with interstimulus intervals of 2-4 min) to the somatic membrane. The Na/Ca exchange inhibitor benzamyl (applied extracellularly, 15-35 microM) and two specific endoplasmic reticulum Ca-ATPase inhibitors, cyclopiazonic acid and thapsigargin (applied intracellularly. 0.1 mM) prevented modification of depression of the ACh current by ouabain (100 microM). It is concluded that Na/Ca exchange and the release of mobilized Ca2+ from intracellular calcium depots are involved in the mechanism by which the Na,K pump controls the depression of neuron cholinosensitivity in the cellular analog of habituation.
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PMID:Involvement of Na/Ca exchange and intracellular mobilized Ca2+ in Na,K-pump-mediated control of depression of the cholinosensitivy of common snail neurons [correction of neorons] using a cellular analog of habituation. 1266 81

Secretion of HCO(3)(-) by airway submucosal glands is essential for normal liquid and mucus secretion. Because the liquid bathing the airway surface (ASL) is acidic, it has been proposed that the surface epithelium may acidify HCO(3)(-)-rich glandular fluid. The aim of this study was to investigate the mechanisms by which intact distal bronchi, which contain both surface and glandular epithelium, modify pH of luminal fluid. Distal bronchi were isolated from pig lungs, cannulated in a bath containing HCO(3)(-)-buffered solution, and perfused continually with an aliquot of similar, lightly buffered solution (LBS) in which NaCl replaced NaHCO(3)(-) (pH 7 with NaOH). The pH of this circulating LBS initially acidified (by 0.053 +/- 0.0053 pH units) and transepithelial potential difference (PD) depolarized. The magnitude of acidification was increased when pH(LBS) was higher. This acidification was unaffected by luminal dimethylamiloride (DMA, 100 microM) but was inhibited by 100 nM bafilomycin A(1) (by 76 +/- 13%), suggesting involvement of vacuolar-H(+) ATPase. Addition of ACh (10 microM) evoked alkalinization of luminal LBS and hyperpolarization of transepithelial PD. The alkalinization was inhibited in HCO(3)(-)-free solutions containing acetazolamide (1 mM) and by DMA and was enhanced by bumetanide (100 microM), an inhibitor of Cl(-) secretion. The hyperpolarization was unaffected by these maneuvers. The anion channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate (300 microM) and combined treatment with DMA and bumetanide blocked both the alkalinization and hyperpolarization responses to ACh. These results are consistent with earlier studies showing that ACh evokes glandular secretion of HCO(3)(-) and Cl(-). Isolated distal airways thus secrete both acid and base equivalents.
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PMID:Secretion of acid and base equivalents by intact distal airways. 1267 70

Transient receptor potential channel (TRPC) genes encode Ca(2+)-permeable channels mediating capacitative Ca(2+) entry (CCE), which maintains intracellular Ca(2+) stores. We compared TRPC gene expression and CCE in human esophageal body (EB) and lower esophageal sphincter (LES), because these smooth muscles have distinct contractile functions that are likely associated with different Ca(2+) regulatory mechanisms. Circular layer smooth muscle cells were grown in primary culture. Transcriptional expression of TRPC genes was compared by semiquantitative RT-PCR. CCE was measured by fura 2 Ca(2+) fluorescence after blockade of sarcoplasmic reticulum Ca(2+)-ATPase with thapsigargin. mRNA for TRPC1, TRPC3, TRPC4, TRPC5, and TRPC6 was identified in EB and LES. TRPC3 and TRPC4 were more abundant in LES than EB. Basal concentration of free intracellular Ca(2+) ([Ca(2+)](i)) was similar in cells from LES (138 +/- 8 nmol/l) and EB (110 +/- 6 nmol/l) and increased with ACh (10 micromol/l; 650 +/- 28 and 590 +/- 21 nmol/l, respectively). With zero Ca(2+) in bath, thapsigargin (2 micromol/l) increased [Ca(2+)](i) more in LES (550 +/- 22 nmol/l) than EB (250 +/- 15 nmol/l, P < 0.001). Subsequent external application of 1 mmol/l Ca(2+) increased [Ca(2+)](i) more in LES (585 +/- 35 nmol/l) than EB (295 +/- 21 nmol/l, P < 0.001), indicating enhanced CCE in LES. This demonstrates CCE and TRPC transcriptional expression in human esophageal smooth muscle. In LES cells, enhanced CCE and expression of TRPC3 and TRPC4 may contribute to the physiological characteristics that distinguish LES from EB.
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PMID:Enhanced capacitative calcium entry and TRPC channel gene expression in human LES smooth muscle. 1273 51

We used optical recording with a Ca(2+)-sensitive dye, fura2, in living slice preparations from the newt retina at different stages of regeneration. ACh produced the most pronounced [Ca2+]i rise in progenitor cells and premature ganglion cells of the earlier stage of retinal regeneration, but less pronounced Ca2+ response in ganglion cells just before, or at the beginning of, synaptogenesis. The [Ca2+]i rise to ACh was mediated by mAChRs. This was shown by inhibition of the ACh-induced Ca2+ response with a preincubation of the mAChR antagonist atropine as well as with direct stimulation of the [Ca2+]i rise by the mAChR agonist muscarine. This muscarine-induced [Ca2+]i rise was more greatly suppressed by the M1 and/or M3 preferring mAChR antagonists than by the M2 preferring mAChR antagonist. The [Ca2+]i rise due to muscarine was not suppressed in the absence of extracellular Ca2+, but suppressed in part in the presence of the L-type voltage-gated Ca2+ channel blockers, verapamil or nicardipine. Furthermore, thapsigargin (TG), a Ca-ATPase inhibitor, abolished the muscarine-induced [Ca2+]i rise in the absence of extracellular Ca2+. These results suggest that the mAChR-mediated [Ca2+]i rise is mainly a result of a release of Ca2+ from intracellular stores. TG produced a slow rise in the resting level of [Ca2+]i. This [Ca2+]i raise was suppressed as extracellular Ca2+ was omitted, whereas a rapid rise in [Ca2+]i occurred when extracellular Ca2+ was reintroduced, suggesting the occurrence of the capacitative Ca2+ influx in the progenitor cells and premature ganglion cells of the regenerating newt retina.
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PMID:Muscarinic calcium mobilization in the regenerating retina of adult newt. 1451 94

Within muscular equivalents of cat lower esophageal sphincter (LES), the circular muscle develops greater spontaneous tone, whereas the sling muscle is more responsive to cholinergic stimulation. Smooth muscle contraction involves a combination of calcium release from stores and of calcium entry via several pathways. We hypothesized that there are differences in the sources of Ca(2+) used for contraction in sling and circular muscles and that these differences could contribute to functional asymmetry observed within LES. Contraction of muscle strips from circular and sling regions of LES was assessed in the presence of TTX. In Ca(2+)-free Krebs, tone was inhibited to a greater degree in circular than sling muscle. L-type Ca(2+) channel blockade with nifedipine or verapamil inhibited tone in LES circular but not sling muscle. Sarcoplasmic reticulum (SR) Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA) caused greater increase in tone in sling than in circular muscle. The phospholipase C inhibitor U-73122 and the SR inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptor blocker 2-aminoethoxydiphenyl borate (2-APB) inhibited tone in circular and sling muscles, demonstrating that continuous release of Ca(2+) from Ins(1,4,5)P(3)-sensitive stores is important in tone generation in both muscles. In Ca(2+)-free Krebs, ACh-induced contractions (AChC) were inhibited to a greater degree in sling than circular muscles. However, nifedipine and verapamil greatly inhibited AChC in the circular but not sling muscle. Depletion of SR Ca(2+) stores with CPA or inhibition of Ins(1,4,5)P(3)-mediated store release with either U-73122 or 2-APB inhibited AChC in both muscles. We demonstrate that LES circular and sling muscles 1) use intracellular and extracellular Ca(2+) sources to different degrees in the generation of spontaneous tone and AChC and 2) use different Ca(2+) entry pathways. These differences hold the potential for selective modulation of LES tone in health and disease.
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PMID:Calcium source diversity in feline lower esophageal sphincter circular and sling muscle. 1456 70

We tested the hypothesis that previously demonstrated gender differences in ACh-induced vascular relaxation could involve diverse Na(+)-K(+)-ATPase functions. We determined Na(+)-K(+)-ATPase by measuring arterial ouabain-sensitive 86Rb uptake in response to ACh. We found a significant increase of Na+ pump activity only in aortic rings from female rats (control 206 +/- 11 vs. 367 +/- 29 nmol 86Rb/K.min(-1).g wt tissue(-1); P < 0.01). Ovariectomy eliminated sex differences in Na(+)-K(+)-ATPase function, and chronic in vivo hormone replacement with 17beta-estradiol restored the ACh effect on Na(+)-K(+)-ATPase. Because ACh acts by enhancing production of NO, we examined whether the NO donor sodium nitroprusside (SNP) mimics the action of ACh on Na(+)-K(+)-ATPase activity. SNP increased ouabain-sensitive 86Rb uptake in denuded female arteries (control 123 +/- 7 vs. 197 +/- 12 nmol 86Rb/K.min(-1).g wt tissue(-1); P < 0.05). Methylene blue (an inhibitor of guanylate cyclase) and KT-5823 (a cGMP-dependent kinase inhibitor) blocked the stimulatory action of SNP. Exposure of female thoracic aorta to the Na+/K+ pump inhibitor ouabain significantly decreased SNP-induced and ACh-mediated relaxation of aortic rings. At the molecular level, Western blot analysis of arterial tissue revealed significant gender differences in the relative abundance of catalytic isoforms of Na(+)-K(+)-ATPase. Female-derived aortas exhibited a greater proportion of alpha2-isoform (44%) compared with male-derived aortas. Furthermore, estradiol upregulated the expression of alpha2 mRNA in male arterial explants. Our results demonstrate that enhancement of ACh-induced relaxation observed in female rats may be in part explained by 1) NO-dependent increased Na(+)-K(+)-ATPase activity in female vascular tissue and 2) greater abundance of Na(+)-K(+)-ATPase alpha2-isoform in females.
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PMID:Estradiol-induced expression of N(+)-K(+)-ATPase catalytic isoforms in rat arteries: gender differences in activity mediated by nitric oxide donors. 1470 24

It has been shown that lobeline (alpha-lobeline) is a lipophilic, nonpyridine, naturally occurring alkaloid obtained from Indian tobacco, Lobelia inflata. The present study was attempted to investigate the effect of lobeline on secretion of catecholamines (CA) evoked by ACh, high K(+), 1.1-dimethyl-4-phenyl piperazinium iodide (DMPP) and (3-(m-chloro-phenyl-carbamoyl-oxy)-2-butynyl trimethyl ammonium chloride (McN-A-343) from the isolated perfused rat adrenal gland and to establish the mechanism of its action. l-Lobeline (30-300 microM) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition in CA secretory responses evoked by ACh (5.32 x 10(-3) M), DMPP (10(-4) M for 2 min) and McN-A-343 (10(-4) M for 2 min). However, lower dose of lobeline did not affect CA secretion by high K(+) (5.6 x 10(-2) M), higher dose of it reduced greatly CA secretion of high K(+). l-Lobeline itself did also fail to affect basal catecholamine output. Furthermore, in adrenal glands loaded with lobeline (100 microM), CA secretory response evoked by methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (Bay-K-8644), an activator of L-type Ca(2+) channels was markedly inhibited while CA secretion by cyclopiazonic acid, an inhibitor of cytoplasmic Ca(2+)-ATPase was not affected. However, nicotine (30 microM), given into the adrenal gland for 60 min, initially rather enhanced CA secretory responses evoked by ACh (5.32 x 10(-3) M) and high K(+) (5.6 x 10(-2) M) followed by great inhibition later, while responses evoked by DMPP (10(-4) M for 2 min) and McN-A-343 (10(-4) M for 2 min) were greatly inhibited. Taken together, these results suggest that lobeline inhibits greatly CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors. Lobeline at lower dose does not affect that by membrane depolarization, but at larger dose inhibits that. It is thought that this inhibitory effect of lobeline may be mediated by blocking the calcium influx into the rat adrenal medullary chromaffin cells without the inhibition of Ca(2+) release from the cytoplasmic calcium store, which is relevant to its nicotinic antagonistic activity. It also seems that there is a difference in the mode of action between nicotine and lobeline in rat adrenomedullary CA secretion.
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PMID:Influence of lobeline on catecholamine release from the isolated perfused rat adrenal gland. 1476 22

Acetylcholine (ACh) hyperpolarized the rat diaphragm muscle fibers by 4.5 +/- 0.8 mV (K0.5 = = 36 +/- 6 nmol/l). The AC-induced hyperpolarization was blocked by d-tubocurarine and ouabain in nanomolar concentrations. This effect of ACh was not observed in cultured C2C12 muscle cells and in Xenopus oocytes with expressed embryonic mouse muscle nicotinic acetylcholine receptors (nAChR) or with neuronal alpha 4 beta 2 nAChR. In membrane preparations from the Torpedo californica electric organ, containing both nAChR and Na, K-ATPase, 10 nmol/l ouabain modulated the binding kinetics of the cholinergic ligand dansyl-C6-choline to the nAChR. These results suggest that in-sensitive alpha 2 isoform) and nAChR in a state with high affinity to Ach and d-tubocurarine may form a functional complex in which binding of ACh to nAchR is coupled to activation of the Na, K-ATPase.
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PMID:[Functional interaction between nicotinic cholinergic receptors and Na, K-ATPase in the skeletal muscles]. 1514 93


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