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首页> 外文学位 >Osteoblastic voltage-sensitive calcium channels mediate the actions of 1,25-dihydroxyvitamin D3 during bone remodeling.
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Osteoblastic voltage-sensitive calcium channels mediate the actions of 1,25-dihydroxyvitamin D3 during bone remodeling.

机译：成骨细胞电压敏感的钙通道介导1,25-二羟基维生素D3在骨骼重塑过程中的作用。

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摘要

VSCCs open in response to external stimuli, including calcitropic hormones, which alter plasma membrane Ca2+ permeability. Ca2+ that enters cells through these channels serves a second messenger function, eliciting responses including secretion and gene expression changes. In osteoblasts, VSCCs serve as key regulators of Ca2+ permeability and are a major class of calcitropic hormone-sensitive plasma membrane Ca 2+ channels. VSCCs exist as complexes of polypeptide subunits comprised of a pore-forming α1 subunit, an intracellular β subunit, a dimer of α2 and δ subunits, and in some tissues, a γ subunit. Previous studies demonstrated that the activity of the α 1C subunit of the L-type VSCC rapidly modulates Ca2+ permeability in proliferating osteoblasts. In this dissertation, I identified which α1 subunits are expressed in mouse osteoblastic cells and quantified expression changes following 1,25(OH)2D3 treatment. Of the nine α1 subunits expressed in osteoblasts, there are decreases in expression for the α1C and the T-type α 1G subunits, and an increase in the expression of the T-type α 1H subunit, following 24 hr 1,25(OH)2D3 treatment. Ca2+ influx assays corroborate the shift from an L-type dominant to a T-type dominant state. RT-PCR and immunohistochemistry assays measured mRNA and protein expression of auxiliary subunits. Results indicate that osteoblastic cells express multiple β subunits and α2δ dimers, but no γ subunits. We propose a structure for the functional osteoblast VSCC consisting of α1, β, α2δ subunits and devoid of a γ subunit.; The balance of osteoblast and osteoclast activity maintains bone density through the activity of OPG and RANKL. In this dissertation, we measured changes in expression and secretion of OPG in MC3T3-E1 cells and calvarial organ cultures following treatment with 1,25(OH)2D3 and inhibitors to VSCCs and Ca2+-regulated signaling pathways. In both systems, OPG secretion significantly decreased following 24 hr 1,25(OH)2D 3 treatment, by inhibitors of L-type VSCCs and by CaMK, but not by inhibitors of PKA, MAPK, or other families of VSCCs. OPG secretion is abrogated by transfection with decoy CRE binding sites. My results suggest that OPG secretion is regulated through CaMK signaling maintained by the activity of the L-type VSCC and is mediated through the CRE-binding protein.
机译：VSCC在外部刺激（包括降钙素）的作用下开放，从而改变细胞膜Ca 2 + 的通透性。通过这些通道进入细胞的Ca 2+ 具有第二种信使功能，引起包括分泌和基因表达变化在内的应答。在成骨细胞中，VSCCs是Ca 2 + 渗透性的关键调节剂，是降钙素敏感性浆膜Ca 2 + 通道的主要类别。 VSCC以多肽亚基的复合物形式存在，这些亚基由形成孔的α 1 亚基，细胞内β亚基，α 2 和δ亚基的二聚体组成，在某些组织中， γ亚基。先前的研究表明，L型VSCC的α 1C 亚基的活性迅速调节了成骨细胞中Ca 2 + 的渗透性。本文确定了小鼠成骨细胞中表达哪些α 1 亚基，并定量了1,2,5（OH） 2 D 3 治疗。在成骨细胞中表达的9个α 1 亚基中，α 1C 和T型α 1G 亚基的表达下降，并且1,25（OH） 2 D 3 处理24小时后T型α 1H 亚基表达增加。 Ca 2 + 流入试验证实了从L型显性状态向T型显性状态的转变。 RT-PCR和免疫组化测定法测量了辅助亚基的mRNA和蛋白质表达。结果表明，成骨细胞表达多个β亚基和α 2 δ二聚体，但不表达γ亚基。我们提出了一种功能性成骨细胞VSCC的结构，该结构由α 1 ，β，α 2 δ亚基组成，不含γ亚基。成骨细胞和破骨细胞活性的平衡通过OPG和RANKL的活性维持骨密度。本文研究了1,25（OH） 2 D 3 和抑制剂处理后MC3T3-E1细胞和颅内器官培养物中OPG的表达和分泌变化对VSCCs和Ca 2 + 调节信号通路的影响在这两个系统中，通过L型VSCC抑制剂和CaMK，经过24小时1,25（OH） 2 D 3 处理后，OPG分泌均显着降低，但不是通过PKA，MAPK或其他VSCC家族的抑制剂。通过诱饵CRE结合位点的转染消除了OPG的分泌。我的结果表明，OPG的分泌受L型VSCC活性维持的CaMK信号传导的调节，并由CRE结合蛋白介导。

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  • 作者

    Bergh, Joel Justin.;

  • 作者单位

    University of Delaware.;

  • 授予单位 University of Delaware.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 168 p.
  • 总页数 168
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

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