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Depolarization-evoked Ca²⁺ release in a non-excitable cell, the rat megakaryocyte

JOURNAL OF PHYSIOLOGY-LONDON 1999年第2期515卷 385-390页

作者： Mahaut-Smith, MP Hussain, JF Mason, MJ Univ Cambridge Dept Physiol Cambridge CB2 3EG England

1. The effect of membrane potential on [Ca2+](i) in rat megakaryocytes was studied using simultaneous whole-cell patch clamp and fura-2 fluorescence recordings. 2. Depolarization from -75 to 0 mV had no effect on [Ca2+](i) in unstimulated cells, but evoked one or more spikes of Ca2+ increase (peak increase: 714 +/- 95 nM) during activation of metabotropic purinoceptors by 1 mu M ADP. 3. The depolarization-evoked Ca2+ increase was present in Ca2+-free medium and also following removal of Na+. Thus depolarization mobilizes Ca2+ from an intracellular store without a requirement for altered Na+-Ca2+ exchange activity. 4. Intracellular dialysis with heparin blocked the depolarization-evoked Ca2+ increase, indicating a role for functional IP3 receptors. 5. Under current clamp, ADP caused the membrane potential to fluctuate between -43 +/- 1 and -76 +/- 1 mV. Under voltage clamp, depolarization from -75 to -45 mV evoked a transient [Ca2+](i) increase (398 +/- 91 nM) during exposure to ADP. 6. We conclude that during stimulation of metabotropic purinoceptors, membrane depolarization over the physiological range can stimulate Ca2+ release from intracellular stores in the rat megakaryocyte, a non-excitable cell type, This may represent an important mechanism by which electrogenic influences can control patterns of [Ca2+](i) increase.

关键词：腺苷二磷酸/药理学钙/代谢电生理学肝素/药理学细胞内膜/代谢巨核细胞/代谢巨核细胞/生理学膜电位/药物作用容积渗克分子浓度膜片钳术大鼠 Wistar 受体嘌呤能/药物作用受体嘌呤能/代谢钠/药理学动物男(雄)性大鼠

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In vitro infection of megakaryocytes and their precursors by human cytomegalovirus

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BLOOD 2000年第2期95卷 487-493页

作者： Crapnell, K Zanjani, ED Chaudhuri, A Ascensao, JL St Jeor, S Maciejewski, JP Univ Nevada Sch Med Dept Cellular & Mol Biol Reno NV 89557 USA Univ Nevada Sch Med Dept Internal Med Reno NV 89557 USA Univ Nevada Sch Med Dept Microbiol Reno NV 89557 USA

Apart from congenital human cytomegalovirus(HCMV) infection, manifest HCMV disease occurs primarily in immunocompromised patients. In allogeneic bone marrow transplantation, HCMV is frequently associated with graft failure and cytopenias involving all hematopoietic lineages, but thrombocytopenia is the most commonly reported hematologic complication. The authors hypothesized that megakaryocytes (MK) may be a specific target for HCMV, Although the susceptibility of immature hematopoietic progenitors cells to HCMV has been established, a productive viral life cycle has only been linked to myelomonocytic maturation. The authors investigated whether HCMV can also infect MK and impair their function. They demonstrated that HCMV did not affect the thrombopoietin (TPO)-driven proliferation of CD34(+) cells until MK maturation occurred. MK challenged with HCMV showed a 50% more rapid loss of viability than mock-infected cells. MK and their early precursors were clearly shown to be susceptible to HCMV in vitro, as evidenced by the presence of HCMV in magnetic column-purified CD42(+) MK and P-color fluorescent staining with antibodies directed against CD42a and HCMV pp65 antigen, These findings were confirmed by the infection of MK with a laboratory strain of HCMV containing the beta-galactosidase (beta-gal) gene. Using chromogenic beta-gal substrates, HCMV was detected during MK differentiation of infected CD34(+) cells and after infection of fully differentiated MK, Production of infectious virus was observed in cultures infected MK, suggesting that HCMV can complete its life cycle. These results demonstrate that MK are susceptible to HCMV infection and that direct infection of these cells in vivo may contribute to the thrombocytopenia observed in patients infected with HCMV. (Blood. 2000;95:487-493) (C) 2000 by The American Society of Hematology.

关键词：抗原 CD/分析抗原 CD34/分析骨髓细胞/细胞学细胞分裂细胞分离/方法细胞培养的巨细胞病毒/遗传学巨细胞病毒/致病力巨细胞病毒/生理学 DNA 病毒/分析造血干细胞/细胞学造血干细胞/生理学造血干细胞/病毒学生命周期各时期巨核细胞/细胞学巨核细胞/生理学巨核细胞/病毒学聚合酶链反应重组蛋白质类/生物合成转染病毒蛋白质类/分析 β半乳糖苷酶类/生物合成 β半乳糖苷酶类/遗传学人类

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A novel role for membrane potential in the modulation of intracellular Ca²⁺ oscillations in rat megakaryocytes

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第2期524卷 437-446页

作者： Mason, MJ Hussain, JF Mahaut-Smith, MP Univ Cambridge Dept Physiol Cambridge CB2 3EG England

1. The effect of membrane potential (V-m) on ADP-evoked [Ca2+](i) oscillations was investigated in rat megakaryocytes, a non-excitable cell type recently shown to exhibit depolarisation evoked Ca2+ release from intracellular stores during metabotropic purinoceptor stimulation. 2. Hyperpolarising voltage steps caused a transient fall in [Ca2+](i) and either abolished Ca2+ oscillations or reduced the oscillation amplitude. These effects were observed in both the presence and absence of extracellular Ca2+ and also in Na+-free saline solutions, suggesting that hyperpolarisation leads to a reduction in the level of ADP-dependent Ca2+ release without a requirement for altered transmembrane Ca2+ fluxes. 3. In the presence of Ca2+ oscillations, depolarising voltage steps transiently enhanced the amplitude of Ca2+ oscillations. Following run-down of Ca2+ oscillations, depolarisation briefly restimulated oscillations. 4. Simultaneous [Ca2+](i) and current-clamp recordings showed that Ca2+ and V-m oscillate in synchrony, with an average fluctuation of approximately 30-40 mV, due to activation and inactivation of Ca2+-dependent K+ channels. Application of a physiological oscillating V-m waveform to non-oscillating cells under voltage clamp stimulated [Ca2+](i) oscillations. 5. Analysis of the relationship between [Ca2+](i) and V-m showed a threshold for activation of hyperpolarisation at about 250-300 nM. The implications of this threshold in the interaction between V-m and Ca2+ release during oscillations are discussed. 6. We conclude that the ability of voltage to control release of endosomal Ca2+ in ADP-stimulated megakaryocytes is bipolar in nature. Our data suggest that V-m changes are active components of the feedback/feedforward mechanisms contributing to the generation of Ca2+ oscillations.

关键词：腺苷二磷酸/药理学钙信号/药物作用钙信号/生理学动力学巨核细胞/药物作用巨核细胞/生理学膜电位/药物作用膜电位/生理学显微镜检查荧光膜片钳术大鼠 Wistar 受体嘌呤能/药物作用钠/代谢动物男(雄)性大鼠

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Megakaryocyte hyperplasia and enhanced agonist-induced platelet activation in vasodilator-stimulated phosphoprotein knockout mice

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第14期96卷 8120-8125页

作者： Hauser, W Knobeloch, KP Eigenthaler, M Gambaryan, S Krenn, V Geiger, J Glazova, M Rohde, E Horak, I Walter, U Zimmer, M Univ Wurzburg Inst Klin Biochem & Pathobiochem D-97080 Wurzburg Germany Univ Wurzburg Inst Pathol D-97080 Wurzburg Germany Forschungsinst Mol Pharmakol Abt Mol Genet D-12207 Berlin Germany Russian Acad Sci IM Sechenov Evolutionary Physiol & Biochem Inst St Petersburg 194223 Russia

Vasodilator-stimulated phosphoprotein (VASP), a substrate of cAMP- and cGMP-dependent protein kinases, is associated with focal adhesions, cell-cell contacts, microfilaments,and highly dynamic membrane regions. VASP, which is expressed in most cell types and in particularly high levels inhuman platelets, binds to profilin, zyxin, vinculin, F-actin, and the Listeria monocytogenes surface protein ActA. VASP is a member of the enabled (Ena)/VASP protein family and is thought to be involved in actin filament formation and integrin alpha(IIb)beta(3) inhibition in human platelets. To gain further insight into the in vivo function of this protein, VASP-deficient mice were generated by homologous recombination. VASP-/- mice demonstrated hyperplasia of megakaryocytes in bone marrow and spleen but exhibited no other macroscopic or microscopic abnormalities. Activation of platelets with thrombin induced a more than 2-fold higher surface expression of P-selectin and fibrinogen binding in VASP-deficient platelets in comparison to wild type. These data support the concept that VASP is a negative modulator of platelet and integrin alpha(IIb)beta(3) activation. Although the limited phenotypic differences between wild-type and VASP-/- mice suggested functional compensation of VASP by members of the Ena/VASP family, alterations in the expression levels of mammalian enabled (Mena) and Ena-VASP-like (Evl) protein were not detected. VASP-deficient mice may provide an interesting model system for diseases in which enhanced platelet activation plays a major role.

关键词：血小板/生理学载体蛋白质类/遗传学载体蛋白质类/代谢细胞黏附分子/遗传学细胞黏附分子/生理学 DNA引物 DNA 互补增生巨核细胞/病理学巨核细胞/生理学小鼠基因敲除微丝蛋白质类器官特异性磷蛋白类/遗传学磷蛋白类/生理学血小板活化/生理学聚合酶链反应蛋白质结合限制性内切酶图谱法动物女(雌)性人类男(雄)性小鼠

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Transforming growth factor-β1 (TGF-β1) induces thrombopoietin from bone marrow stromal cells, which stimulates the expression of TGF-β receptor on megakaryocytes and, in turn, renders them susceptible to suppression by TGF-β itself with high specificity

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BLOOD 1999年第6期94卷 1961-1970页

作者： Sakamaki, S Hirayama, Y Matsunaga, T Kuroda, H Kusakabe, T Akiyama, T Konuma, Y Sasaki, K Tsuji, N Okamoto, T Kobune, M Kogawa, K Kato, J Takimoto, R Koyama, R Niitsu, Y Sapporo Med Univ Sch Med Dept Internal Med 4 Chuo Ku Sapporo Hokkaido 0608543 Japan Hokkaido Prefectural Sapporo Kitano Hosp Sapporo Hokkaido Japan

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-beta 1 (TGF-beta 1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-beta receptors I and II on megakaryoblasts at the midmegakaryopoietic stage;at this stage, TGF-beta 1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg), This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit-granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-beta 1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-beta 1 is one of the pathophysiological feedback regulators of megakaryopoiesis, (C) 1999 by The American Society of Hematology.

关键词：骨髓/病理学集落形成单位测定红细胞生成素重组/药理学基因表达调控/药物作用粒细胞集落刺激因子重组/药理学血细胞生成白细胞介素3/药理学白细胞介素6/药理学巨核细胞/细胞学巨核细胞/病理学巨核细胞/生理学模型生物学紫癜血小板减少性/遗传学紫癜血小板减少性/代谢紫癜血小板减少性/病理学 RNA 信使/遗传学重组蛋白质类/药理学参考值间质细胞/细胞学间质细胞/药物作用间质细胞/生理学血小板生成素/生物合成血小板生成素/遗传学转录遗传转化生长因子β/药理学肿瘤坏死因子α/药理学人类

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