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Critical events in the life cycle of malaria parasites are controlled by calcium‐dependent signalling cascades, yet the molecular mechanisms of calcium release remain poorly understood. The synchronized development of Plasmodium berghei gametocytes relies on rapid calcium release from internal stores within 10 s of gametocytes being exposed to mosquito‐derived xanthurenic acid (XA). Here we addressed the function of phosphoinositide‐specific phospholipase C (PI‐PLC) for regulating gametocyte activation. XA triggered the hydrolysis of PIP2 and the production of the secondary messenger IP3 in gametocytes. Both processes were selectively blocked by a PI‐PLC inhibitor, which also reduced the early Ca2+ signal. However, microgametocyte differentiation into microgametes was blocked even when the inhibitor was added up to 5 min after activation, suggesting a requirement for PI‐PLC beyond the early mobilization of calcium. In contrast, inhibitors of calcium release through ryanodine receptor channels were active only during the first minute of gametocyte activation. Biochemical determination of PI‐PLC activity was confirmed using transgenic parasites expressing a fluorescent PIP2/IP3 probe that translocates from the parasite plasmalemma to the cytosol upon cell activation. Our study revealed a complex interdependency of Ca2+ and PI‐PLC activity, with PI‐PLC being essential throughout gamete formation, possibly explaining the irreversibility of this process. 相似文献
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Tokuhisa Abo Ryo‐hei Iida Syuhei Kaneko Takeo Suga Hiroyuki Yamada Yoshiki Hamada Akira Yamane 《Cell biochemistry and function》2012,30(8):671-676
Clenbuterol, a β2‐adrenergic agonist, increases the hypertrophy of skeletal muscle. Insulin‐like growth factor (IGF) is reported to work as a potent positive regulator in the clenbuterol‐induced hypertrophy of skeletal muscles. However, the precise regulatory mechanism for the hypertrophy of skeletal muscle induced by clenbuterol is unknown. Myostatin, a member of the TGFβ super family, is a negative regulator of muscle growth. The aim of the present study is to elucidate the function of myostatin and IGF in the hypertrophy of rat masseter muscle induced by clenbuterol. To investigate the function of myostatin and IGF in regulatory mechanism for the clenbuterol‐induced hypertrophy of skeletal muscles, we analysed the expression of myostatin and phosphorylation levels of myostatin and IGF signaling components in the masseter muscle of rat to which clenbuterol was orally administered for 21 days. Hypertrophy of the rat masseter muscle was induced between 3 and 14 days of oral administration of clenbuterol and was terminated at 21 days. The expression of myostatin and the phosphorylation of smad2/3 were elevated at 21 days. The phosphorylation of IGF receptor 1 (IGFR1) and akt1 was elevated at 3 and 7 days. These results suggest that myostatin functions as a negative regulator in the later stages in the hypertrophy of rat masseter muscle induced by clenbuterol, whereas IGF works as a positive regulator in the earlier stages. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
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Miriam Capri Maria Lorenzi Gianluca Fulgenzi Maria C. Albertini Stefano Salvioli Markku J. Alen Urho M. Kujala Giulia Borghetti Lucia Babini Jaakko Kaprio Sarianna Sipilä Claudio Franceschi Vuokko Kovanen Antonio D. Procopio 《Aging cell》2014,13(5):850-861
MiRNAs are fine‐tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co‐twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen‐based hormone replacement therapy (HRT) to explore estrogen‐dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62‐years‐old monozygotic female twin pairs discordant for HRT (median 7 years). MCF‐7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR‐182, miR‐223 and miR‐142‐3p expressions in HRT using than in their nonusing co‐twins. Insulin/IGF‐1 signaling emerged one common pathway targeted by these miRNAs. IGF‐1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR‐182 and miR‐223 on IGF‐1R and FOXO3A mRNA as well as a dose‐dependent miR‐182 and miR‐223 down‐regulations concomitantly with up‐regulation of FOXO3A and IGF‐1R expression. Novel finding is the postmenopausal HRT‐reduced miRs‐182, miR‐223 and miR‐142‐3p expression in female skeletal muscle. The observed miRNA‐mediated enhancement of the target genes' IGF‐1R and FOXO3A expression as well as the activation of insulin/IGF‐1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women. 相似文献
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《Autophagy》2013,9(7):912-921
T cell receptor activation induces inositol 1,4,5 trisphosphate (IP3)-mediated calcium signaling that is essential for cell metabolism and survival. Moreover, inhibitors of IP3 or pharmacological agents that disrupt calcium homeostasis readily induce autophagy. Using a glucocorticoid-sensitive CD4/CD8 positive T cell line, we found that dexamethasone prevented both IP3-mediated and spontaneous calcium signals within a timeframe that correlated with the induction of autophagy. We determined that this loss in IP3-mediated calcium signaling was dependent upon the downregulation of the Src kinase Fyn at the mRNA and protein level. Because it has previously been shown that Fyn positively regulates IP3-mediated calcium release by phosphorylating Type I IP3 receptors (IP3R1), we investigated the effect of glucocorticoids on IP3R1 phosphorylation at Tyr353. Accordingly, glucocorticoid-mediated downregulation of Fyn prevented IP3R1 phosphorylation at Tyr353. Moreover, selective knockdown of Fyn or treatment with a Src inhibitor also attenuated IP3-mediated calcium release and induced autophagy. Collectively, these data indicate that glucocorticoids promote autophagy by inhibiting IP3-dependent calcium signals. These findings carry important therapeutic implications given the widespread use of dexamethasone as both a chemotherapeutic and immunosuppressive agent. 相似文献
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Ondrias K Lencesova L Sirova M Labudova M Pastorekova S Kopacek J Krizanova O 《Journal of cellular physiology》2011,226(12):3147-3155
Inositol 1,4,5‐trisphosphate (IP3) receptors are emerging as key sites for regulation by pro‐ and anti‐apoptotic factors. Induction of apoptosis for 3 h increased mRNA and protein levels of type 1 IP3 receptors in non‐differentiated (ND), but not in differentiated (D) PC12 cells. Inhibitors of the IP3R's calcium release—2‐aminoethoxydiphenyl borate (2‐APB) and xestospongin—completely prevented Bax and caspase‐3 mRNA increase after treatment with the apoptosis inducer set (AIK), and this reinforces the importance of IP3R1 in the apoptosis of ND PC12 cells. Apoptosis induction not only increases the IP3R1 protein, but it also causes formation of IP3R1 clusters in the nucleus which most likely result from fusion of the nucleoplasmic reticulum and/or IP3R1 translocation to the nucleus. This is quite similar to the observations noted after overexpression of IP3R1 in PC12 cells. The amount of IP3 induced calcium release was higher in control than in AIK‐treated cells. From our results we propose that after the apoptosis induction the amount of intranuclear calcium decreased dramatically due to the increase of calcium permeability of the nuclear calcium store vesicles. Therefore, increase of the calcium permeability may result from IP3 receptors translocation to nuclei that can boost the calcium transport through IP3 receptors. J. Cell. Physiol. 226: 3147–3155, 2011. © 2011 Wiley Periodicals, Inc. 相似文献
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IRBIT is an inositol 1,4,5‐trisphosphate (IP3) receptor (IP3R)‐binding protein that inhibits the activation of IP3R by competing with IP3 for the common binding site on IP3R. In this study, we characterize an IRBIT homologue, termed Long‐IRBIT. Long‐IRBIT is highly homologous to IRBIT (~88%) and heteromerizes with IRBIT. In spite of complete conservation of critical amino acids required for the interaction with IP3R and comparable phosphorylations on critical four Ser residues for IP3R‐binding, Long‐IRBIT retains little ability to interact with IP3R. Deletion mutagenesis analysis revealed that this low affinity to IP3R is attributable to an inhibitory effect of the Long‐IRBIT specific N‐terminal appendage (LISN domain). Immunohistochemical analysis revealed the distinct distribution of Long‐IRBIT and IRBIT in mouse cerebellar cortex, that is, Long‐IRBIT is mainly expressed in interneurons such as basket cells, while IRBIT is mainly expressed in glial cells. Furthermore, Long‐IRBIT, but not IRBIT, underwent phosphorylation during neuronal differentiation in neuroblastoma cells and this phosphorylation was dependent on the LISN domain. These results suggest that Long‐IRBIT has a different function from IRBIT. 相似文献
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Michael W Harr Karen S McColl Fei Zhong Jason K Molitoris Clark W Distelhorst 《Autophagy》2010,6(7):912-921
T cell receptor activation induces inositol 1,4,5 trisphosphate (IP3)-mediated calcium signaling that is essential for cell metabolism and survival. Moreover, inhibitors of IP3 or pharmacological agents that disrupt calcium homeostasis readily induce autophagy. Using a glucocorticoid-sensitive CD4/CD8 positive T cell line, we found that dexamethasone prevented both IP3-mediated and spontaneous calcium signals within a timeframe that correlated with the induction of autophagy. We determined that this loss in IP3-mediated calcium signaling was dependent upon the downregulation of the Src kinase Fyn at the mRNA and protein level. Because it has previously been shown that Fyn positively regulates IP3-mediated calcium release by phosphorylating Type I IP3 receptors (IP3R1), we investigated the effect of glucocorticoids on IP3R1 phosphorylation at Tyr353. Accordingly, glucocorticoid-mediated downregulation of Fyn prevented IP3R1 phosphorylation at Tyr353. Moreover, selective knockdown of Fyn or treatment with a Src inhibitor also attenuated IP3-mediated calcium release and induced autophagy. Collectively, these data indicate that glucocorticoids promote autophagy by inhibiting IP3-dependent calcium signals. These findings carry important therapeutic implications given the widespread use of dexamethasone as both a chemotherapeutic and immunosuppressive agent.Key words: autophagy, calcium, Fyn, IP3 receptor, dexamethasone 相似文献
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Zhongjian Xie Jian Peng Ying Chen 《Biochemical and biophysical research communications》2010,399(3):425-476
Phospholipase C-γ1 (PLC-γ1), a tyrosine kinase substrate, has been implicated in the pathway for the epidermal growth factor receptor (EGFR)-induced cell migration. However, the underlying mechanism by which PLC-γ1 mediates EGFR-induced cell migration remains elusive. In the present study, we sought to determine whether the lipase activity of PLC-γ1 is required for EGFR-induced cell migration. We found that overexpression of PLC-γ1 in squamous cell carcinoma SCC4 cells markedly enhanced EGF-induced PLC-γ1 activation, intracellular calcium rise, and cell migration. This enhancement was abolished by mutational inactivation of the catalytic domain of PLC-γ1. Inhibition of the downstream signaling processes mediated by the activity of phospholipase C (PLC) using IP3 receptor inhibitor or intracellular calcium chelator blocked EGF-induced cell migration. These data indicate that EGF-induced cell migration is mediated by the lipase domain of PLC-γ1 and the subsequent IP3 generation and intracellular calcium mobilization. 相似文献
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Yanli Nie Feifei Huang Shujun Dong Lin Li Ping Gao Heping Zhao Yingdian Wang Shengcheng Han 《Proteomics》2014,14(20):2335-2338
Inositol 1,4,5‐trisphosohate (IP3) and its receptors play a pivotal role in calcium signal transduction in mammals. However, no homologs of mammalian IP3 receptors have been found in plants. In this study, we isolated the microsomal fractions from rice cells in suspension culture and further obtained putative IP3‐binding proteins by heparin‐agarose affinity purification. The IP3‐binding activities of these protein fractions were determined by [3H] IP3‐binding assay. SDS‐PAGE and MS analysis were then performed to characterize these proteins. We have identified 297 proteins from the eluates of heparin‐agarose column chromatography, which will provide insight into the IP3 signaling pathways in plants. All MS data have been deposited in the ProteomeXchange with identifier PXD000763 ( http://proteomecentral.proteomexchange.org/dataset/PXD000763 ). 相似文献
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Expression of myostatin in the spotted rose snapper Lutjanus guttatus during larval and juvenile development under cultured conditions
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J. Torres‐Velarde L. Ibarra‐Castro E. Rodríguez‐Ibarra I. Sifuentes‐Romero R. Hernández‐Cornejo A. García‐Gasca 《Journal of fish biology》2015,87(5):1147-1164
In this study, the developmental expression pattern of myostatin (mstn) in the spotted rose snapper Lutjanus guttatus under culture conditions is presented. The full coding sequence of mstn from L. guttatus was isolated from muscle tissue, obtaining 1134 nucleotides which encode a peptide of 377 amino acids. The phylogenetic analysis indicated that this sequence corresponds to mstn‐1. mstn expression was detected in embryonic stages, and maintained at low levels until 28 days post‐hatch, when it showed a significant increase, coinciding with the onset of metamorphosis. After that, expression was fluctuating, coinciding probably with periods of rapid and slow muscle growth or individual growth rates. mstn expression was also analysed by body mass with higher levels detected in smaller animals, irrespective of age. mstn was also expressed in other tissues from L. guttatus, presenting higher levels in brain, eye and gill. In brain for instance, two variants of mstn were isolated, both coding sequences were identical to muscle, except that one of them contained a 75 nucleotide deletion in exon 1, maintaining the reading frame but deleting two conserved cysteine residues. Phylogenetic analysis indicated that this brain variant was also mstn‐1. The function of this variant is not clear and needs further investigation. These results indicate that mstn‐1 participates in different physiological processes other than muscle growth in fishes. 相似文献
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Qiliqiangxin inhibits angiotensin II‐induced transdifferentiation of rat cardiac fibroblasts through suppressing interleukin‐6
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Jingmin Zhou Kun Jiang Xuefeng Ding Mingqiang Fu Shijun Wang Lingti Zhu Tao He Jingfeng Wang Aijun Sun Kai Hu Li Chen Yunzeng Zou Junbo Ge 《Journal of cellular and molecular medicine》2015,19(5):1114-1121
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Insulin‐like growth factor‐1 promotes osteogenic differentiation and collagen I alpha 2 synthesis via induction of mRNA‐binding protein LARP6 expression
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Yue Guo Chen‐Yi Tang Xiao‐Fei Man Hao‐Neng Tang Jun Tang Ci‐La Zhou Shu‐Wen Tan Min Wang Yun‐Zhi Feng Hou‐De Zhou 《Development, growth & differentiation》2017,59(2):94-103
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Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells
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Rebecca L. Adams Aaron C. Mason Laura Glass Aditi Susan R. Wente 《Traffic (Copenhagen, Denmark)》2017,18(12):776-790
The mRNA lifecycle is driven through spatiotemporal changes in the protein composition of mRNA particles (mRNPs) that are triggered by RNA‐dependent DEAD‐box protein (Dbp) ATPases. As mRNPs exit the nuclear pore complex (NPC) in Saccharomyces cerevisiae, this remodeling occurs through activation of Dbp5 by inositol hexakisphosphate (IP6)‐bound Gle1. At the NPC, Gle1 also binds Nup42, but Nup42's molecular function is unclear. Here we employ the power of structure‐function analysis in S. cerevisiae and human (h) cells, and find that the high‐affinity Nup42‐Gle1 interaction is integral to Dbp5 (hDDX19B) activation and efficient mRNA export. The Nup42 carboxy‐terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1‐Dbp5/hDDX19B interaction site. A nup42‐CTD/gle1‐CTD/Dbp5 trimeric complex forms in the presence of IP6. Deletion of NUP42 abrogates Gle1‐Dbp5 interaction, and disruption of the Nup42 or IP6 binding interfaces on Gle1/hGle1B leads to defective mRNA export in S. cerevisiae and human cells. In vitro, Nup42‐CTD and IP6 stimulate Gle1/hGle1B activation of Dbp5 and DDX19B recombinant proteins in similar, nonadditive manners, demonstrating complete functional conservation between humans and S. cerevisiae. Together, a highly conserved mechanism governs spatial coordination of mRNP remodeling during export. This has implications for understanding human disease mutations that perturb the Nup42‐hGle1B interaction. 相似文献