共查询到20条相似文献,搜索用时 15 毫秒
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Yakov Blumenstein Olexandr P. Maximyuk Natalia Lozovaya Natalia M. Yatsenko Nataly Kanevsky Oleg Krishtal Nathan Dascal 《The Journal of physiology》2004,556(1):121-134
N-type voltage-dependent Ca2+ channels (N-VDCCs) play important roles in neurotransmitter release and certain postsynaptic phenomena. These channels are modulated by a number of intracellular factors, notably by Gβγ subunits of G proteins, which inhibit N-VDCCs in a voltage-dependent (VD) manner. Here we show that an increase in intracellular Na+ concentration inhibits N-VDCCs in hippocampal pyramidal neurones and in Xenopus oocytes. In acutely dissociated hippocampal neurones, Ba2+ current via N-VDCCs was inhibited by Na+ influx caused by the activation of NMDA receptor channels. In Xenopus oocytes expressing N-VDCCs, Ba2+ currents were inhibited by Na+ influx and enhanced by depletion of Na+ , after incubation in a Na+ -free extracellular solution. The Na+ -induced inhibition was accompanied by the development of VD facilitation, a hallmark of a Gβγ-dependent process. Na+ -induced regulation of N-VDCCs is Gβγ dependent, as suggested by the blocking of Na+ effects by Gβγ scavengers and by excess Gβγ, and may be mediated by the Na+ -induced dissociation of Gαβγ heterotrimers. N-VDCCs may be novel effectors of Na+ ion, regulated by the Na+ concentration via Gβγ. 相似文献
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A. E. NEL W. DIRIENZO G. F. STEFANINI M. W. WOOTEN G. W. CANONICA G. R. LATTANZE H. C. STEVENSON P. MILLER H. H. FUDENBERG R. M. GALBRAITH 《Scandinavian journal of immunology》1986,24(3):283-290
The potential roles of Ca2+ ions in the response of T lymphocytes to stimulation with monoclonal antisera to the T3 antigen were investigated by means of pharmacological agents that predominantly inhibit the flux of Ca2+ ions into cells (verapamil, nifedipine) or the activity of Ca2+-dependent kinases (trifluoperazine, polymyxin B). As assessed by uptake of [3H]thymidine, proliferation induced with anti-T3 +/- recombinant IL-2 at 72 h was inhibited by greater than 80% in the presence of nifedipine at 50 microM, and almost completely arrested (greater than 95% inhibition) with the other agents at the same concentration. Further quantitative assays of the effects of polymyxin B and trifluoperazine on C-kinase labelling of exogenous substrate showed a major reduction with both agents, but inhibition was substantially greater with polymyxin B that with trifluoperazine (IC50 = 14 and 70 microM respectively). These results were confirmed by qualitative assessment of Ca2+/phospholipid-dependent phosphorylation of endogenous substrates, which demonstrated major phosphoproteins of MW 56,000, 52,000, 43,000, and 20,000, and dose-dependent reduction in labelling in the presence of polymyxin B. Similar results were obtained under more physiological conditions in intact cells labelled with 32P orthophosphate. These findings indicate several possible roles for Ca2+ in T-cell activation, and several possible levels of activity, including modulation of calmodulin-dependent kinases and effects on Ca2+/phospholipid-dependent kinases and Ca2+ channels. 相似文献
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A. Shiraki H. Kume T. Oguma Y. Makino S. Ito K. Shimokata H. Honjo K. Kamiya 《Clinical and experimental allergy》2009,39(2):236-245
Background Isoprostanes are prostaglandin (PG)-like compounds synthesized by oxidative stress, not by cyclooxygenase, and increase in bronchoalveolar lavage fluid of patients with asthma. The airway inflammation implicated in this disease may be amplified by oxidants. Although isoprostanes are useful biomarkers for oxidative stress, the action of these agents on airways has not been fully elucidated. Objective This study was designed to determine the intracellular mechanisms underlying the effects of oxidative stress on airway smooth muscle, focused on Ca2+ signalling pathways involved in the effect of 8-iso-PGF2α. Methods Using simultaneous recording of isometric tension and F340/F380 (an indicator of intracellular concentrations of Ca2+, [Ca2+]i), we examined the correlation between tension and [Ca2+]i in response to 8-iso-PGF2α in the fura-2 loaded tracheal smooth muscle. Results Augmented tension and F340/F380 by 8-iso-PGF2α were attenuated by ICI-192605, an antagonist of thromboxane A2 receptors (TP receptors). Moreover, D609, an antagonist of phosphatidylcholine-specific phospholipase C, markedly reduced both the tension and F340/F380 induced by 8-iso-PGF2α, whereas U73122, an antagonist of phosphatidylinositol-specific phospholipase C, modestly inhibited them by 8-iso-PGF2α. SKF96365, a non-selective antagonist of Ca2+ channels, markedly reduced both tension and F340/F380 by 8-iso-PGF2α. However, diltiazem and verapamil, voltage-dependent Ca2+ channel inhibitors, modestly attenuated tension although their reduction of F340/F380 was not different from that by SKF96365. Y-27632, an inhibitor of Rho-kinase, significantly attenuated contraction induced by 8-iso-PGF2α without reducing F340/F380, whereas GF109203X and Go6983, protein kinase C inhibitors, did not markedly antagonize them although reducing F340/F380 with a potency similar to Y-27632. Conclusion 8-iso-PGF2α causes airway smooth muscle contraction via activation of TP receptors. Ca2+ mobilization by SKF96365- and D609-sensitive Ca2+ influx and Ca2+ sensitization by Rho-kinase contribute to the intracellular mechanisms underlying the action of 8-iso-PGF2α. Rho-kinase may be a therapeutic target for the physiologic abnormalities induced by oxidative stress in airways. 相似文献
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Modulation of spontaneous electrical activities (slow waves, pacemaker potentials and follower potentials) in response to hyperpolarization produced by the ATP-sensitive K+ channel openers (KCOs) pinacidil or nicorandil was investigated in smooth muscle tissues of the guinea-pig stomach antrum. With hyperpolarization, the amplitude of slow waves and follower potentials was reduced and that of pacemaker potentials was increased, with a minor modulation of their frequency. The attenuation of slow waves was associated with an inhibition of the 1st component and abolition of the 2nd component. All these actions of KCOs were antagonized by glibenclamide. An increase in the extracellular K+ concentration prevented the KCO-induced hyperpolarization with partial restoration of slow waves, suggesting that the inhibition was produced mainly by a decrease in membrane resistance. Exposure of tissues to KCOs for a long period of time (> 20 min) resulted in the reappearance of slow waves displaying both 1st and 2nd components. The 2nd component of the slow wave, which displayed a slower recovery, was inhibited again by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-sensitive K+ channels. Noradrenaline hyperpolarized the membrane by activating apamin-sensitive K+ channels and increased the amplitude and frequency of slow waves through activation of α1 -adrenoceptors, actions different from those of KCOs. Thus, inhibition of slow waves by KCOs may be primarily related to the decrease in amplitude of a passive electrotonic component, possibly due to a reduction of the input resistance. The hyperpolarization shifted the threshold potential for generation of the 2nd component of slow waves to negative levels, presumably due to modulation of mitochondrial functions. 相似文献
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Laura Vay Esther Hernández-SanMiguel Jaime Santo-Domingo Carmen D. Lobatón Alfredo Moreno Mayte Montero Javier Alvarez 《The Journal of physiology》2007,580(1):39-49
The recent availability of activators of the mitochondrial Ca2+ uniporter allows direct testing of the influence of mitochondrial Ca2+ uptake on the overall Ca2+ homeostasis of the cell. We show here that activation of mitochondrial Ca2+ uptake by 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) or kaempferol stimulates histamine-induced Ca2+ release from the endoplasmic reticulum (ER) and that this effect is enhanced if the mitochondrial Na+ –Ca2+ exchanger is simultaneously inhibited with CGP37157. This suggests that both Ca2+ uptake and release from mitochondria control the ability of local Ca2+ microdomains to produce feedback inhibition of inositol 1,4,5-trisphosphate receptors (InsP3 Rs). In addition, the ability of mitochondria to control Ca2+ release from the ER allows them to modulate cytosolic Ca2+ oscillations. In histamine stimulated HeLa cells and human fibroblasts, both PPT and kaempferol initially stimulated and later inhibited oscillations, although kaempferol usually induced a more prolonged period of stimulation. Both compounds were also able to induce the generation of Ca2+ oscillations in previously silent fibroblasts. Our data suggest that cytosolic Ca2+ oscillations are exquisitely sensitive to the rates of mitochondrial Ca2+ uptake and release, which precisely control the size of the local Ca2+ microdomains around InsP3 Rs and thus the ability to produce feedback activation or inhibition of Ca2+ release. 相似文献
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