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首页> 外文期刊>Biochemical Pharmacology >Basal ryanodine receptor activity suppresses autophagic flux
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Basal ryanodine receptor activity suppresses autophagic flux

机译：基础ryanodine受体活性抑制自噬助焊剂

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摘要

The inositol 1,4,5-trisphosphate receptors (IP(3)Rs) and intracellular Ca2+ signaling are critically involved in regulating different steps of autophagy, a lysosomal degradation pathway. The ryanodine receptors (RyR), intracellular Ca2+-release channels mainly expressed in excitable cell types including muscle and neurons, have however not yet been extensively studied in relation to autophagy. Yet, aberrant expression and excessive activity of RyRs in these tissues has been implicated in the onset of several diseases including Alzheimer's disease, where impaired autophagy regulation contributes to the pathology. In this study, we determined whether pharmacological RyR inhibition could modulate autophagic flux in ectopic RyR-expressing models, like HEK293 cells and in cell types that endogenously express RyRs, like C2C12 myoblasts and primary hippocampal neurons. Importantly, RyR3 overexpression in HEK293 cells impaired the autophagic flux. Conversely, in all cell models tested, pharmacological inhibition of endogenous or ectopically expressed RyRs, using dantrolene or ryanodine, augmented autophagic flux by increasing lysosomal turn -over (number of autophagosomes and autolysosomes measured as mCherry-LC3 punctaeicell increased from 70.37 +/- 7.81 in control HEK RyR3 cells to 111.18 +/- 7.72 and 98.14 +/- 7.31 after dantrolene and ryanodine treatments, respectively). Moreover, in differentiated C2C12 cells, transmission electron microscopy demonstrated that dantrolene treatment decreased the number of early autophagic vacuoles from 5.9 +/- 2.97 to 1.8 +/- 1.03 per cellular cross section. The modulation of the autophagic flux could be linked to the functional inhibition of RyR channels as both RyR inhibitors efficiently diminished the number of cells showing spontaneous RyR3 activity in the HEK293 cell model (from 41.14% +/- 2.12 in control cells to 18.70% +/- 2.25 and 9.74% +/- 2.67 after dantrolene and ryanodine treatments, respectively). In conclusion, basal RyR-mediated Ca2+-release events suppress autophagic flux at the level of the lysosomes. (C) 2017 Elsevier Inc. All rights reserved.
机译：肌醇1,4,5-三磷酸盐受体（IP（3）Rs）和细胞内Ca2 +信号传导尺寸涉及调节自噬的不同步骤，溶酶体降解途径。然而，瑞那胺受体（Ryr），细胞内Ca2 + - 释放通道主要以肌肉和神经元在包括肌肉和神经元的兴奋细胞类型中表达，但尚未与自噬相比广泛研究。然而，这些组织中Ryrs的异常表达和过量活性在包括阿尔茨海默病的几种疾病的发作中涉及，其中自噬调节受损有助于病理学。在这项研究中，我们确定药理学Ryr抑制是否可以调节异位式Ryr型模型中的自噬助焊剂，如HEK293细胞和内源性表达RγR的细胞类型，如C2C12肌细胞和原发性海马神经元。重要的是，HEK293细胞中的Ryr3过表达损害了自噬助焊剂。相反，在所有的细胞模型中，通过增加溶酶体转动的 - 使用牛核或ryanodine的内源性或异位表达的RγRS的药理抑制（以MCHerry-LC3 Punctaeicell测量的自噬体和自糖瘤的数量增加，增加了70.37 +/- 7.81在对照HEK RYR3细胞中分别为丹参和瑞尼诺治疗后111.18 +/- 7.72和98.14 +/- 7.31。此外，在分化的C2C12细胞中，透射电子显微镜证明掺甘油治疗从5.9 +/- 2.97至1.8 +/- 1.03降低了早期自噬液泡的数量，每蜂窝横截面。随着Ryr抑制剂有效地减少HEK293细胞模型中的细胞数量（对照细胞中的41.14％+/- 2.12，Ryr抑制剂有效地降低了RYR通道的功能抑制，所述自噬磁通量与RYR通道的功能抑制有效地降低了18.70％+ / - 丹参和瑞尼诺治疗后的2.25和9.74％+/- 2.67）。总之，基础Ryr介导的Ca2 + -Release事件抑制溶酶体水平的自噬助焊剂。 （c）2017年Elsevier Inc.保留所有权利。

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  • 来源
    《Biochemical Pharmacology》 |2017年第2017期|共10页
  • 作者

    Vervliet Tim; Pintelon Isabel; Welkenhuyzen Kirsten; Bootman Martin D.; Bannai Hiroko; Mikoshiba Katsuhiko; Martinet Wim; Kasri Nael Nadif; Parys Jan B.; Bultynck Geert;

  • 作者单位

    Katholieke Univ Leuven Lab Mol &

    Cellular Signaling Dept Cellular &

    Mol Med Campus Gasthuisberg;

    Univ Antwerp Lab Cell Biol &

    Histol Dept Vet Sci B-2610 Antwerp Belgium;

    Katholieke Univ Leuven Lab Mol &

    Cellular Signaling Dept Cellular &

    Mol Med Campus Gasthuisberg;

    Open Univ Sch Life Hlth &

    Chem Sci Walton Hall Milton Keynes MK7 6AA Bucks England;

    RIKEN Brain Sci Inst Lab Dev Neurobiol 2-1 Hirosawa Wako Saitama 3510198 Japan;

    RIKEN Brain Sci Inst Lab Dev Neurobiol 2-1 Hirosawa Wako Saitama 3510198 Japan;

    Univ Antwerp Lab Physiopharmacol Dept Pharmaceut Sci B-2610 Antwerp Belgium;

    Radboud Univ Nijmegen Med Ctr Donders Inst Brain Cognit &

    Behav Dept Cognit Neurosci Dept Human;

    Katholieke Univ Leuven Lab Mol &

    Cellular Signaling Dept Cellular &

    Mol Med Campus Gasthuisberg;

    Katholieke Univ Leuven Lab Mol &

    Cellular Signaling Dept Cellular &

    Mol Med Campus Gasthuisberg;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Dantrolene; Ryanodine receptor; Alzheimer's disease; Autophagy; Lysosome; Ca2+;

    机译：Dantrogene;ryanodine受体;阿尔茨海默病;自噬;溶酶体;CA2 +;

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