Negative regulation of gastric proton pump by desialylation suggested by fluorescent imaging with the sialic acid-specific nanoprobe

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  • Fujii Takuto
    Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
  • Shimizu Takahiro
    Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
  • Kushiro Keiichiro
    Department of Bioengineering, School of Engineering, The University of Tokyo
  • Takeshima Hiroshi
    Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Takai Madoka
    Department of Bioengineering, School of Engineering, The University of Tokyo
  • Sakai Hideki
    Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

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Other Title
  • シアル酸蛍光ナノプローブを用いた胃プロトンポンプのネガティブフィードバック機構の可視化
  • シアルサン ケイコウ ナノプローブ オ モチイタ イ プロトンポンプ ノ ネガティブフィードバック キコウ ノ カシカ

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Abstract

<p>Gastric proton pump (H+,K+-ATPase) which is responsible for H+ secretion of gastric acid (HCl) in gastric parietal cells is the major therapeutic target for treatment of acid-related diseases. H+,K+-ATPase consists of two subunits, a catalytic α-subunit (αHK) and a glycosylated β-subunit (βHK). N-glycosylation of βHK is essential for trafficking and stability of αHK in apical membrane of gastric parietal cells. Terminal sialic acid residues on sugar chains have an important role in various cellular functions. Recently, we succeeded in visualizing the sialylation and desialylation dynamics of βHK using a fluorescence bioimaging nanoprobe consisting of biocompatible polymers conjugated with lectins for detecting sialic acid. In H+,K+-ATPase-expressing cell lines, rat gastric mucosa, and primary culture of rat gastric parietal cells, fluorescence imaging of sialic acid with the nanoprobe showed that sialylation of βHK is regulated by intragastric pH and that inhibition of gastric acid secretion induces desialylation of βHK. In biochemical and pharmacological studies, we revealed that enzyme activity of αHK is negatively regulated by desialylation of βHK. Our studies uncovered a novel negative-feedback mechanism of H+,K+-ATPase in which sialic acids of βHK positively regulates H+,K+-ATPase activity, and acidic pH decreases the pump activity by cleaving sialic acids of βHK. In this topic, we introduce the overview of our research using the bioimaging nanoprobe.</p>

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