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Research article

Neuronal calcium sensor proteins are direct targets of the insulinotropic agent repaglinide

Miki OKADA, Daisuke TAKEZAWA, Shuji TACHIBANAKI, Satoru KAWAMURA, Hiroshi TOKUMITSU, Ryoji KOBAYASHI
Biochemical Journal Oct 01, 2003, 375 (1) 87-97; DOI: 10.1042/bj20030376
Miki OKADA
Department of Signal Transduction Sciences, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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Daisuke TAKEZAWA
Institute of Low Temperature Science, Hokkaido University, Kita-19 Nishi-8, Kita-ku, Sapporo 060-0819, Japan
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Shuji TACHIBANAKI
Department of Biology, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
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Satoru KAWAMURA
Department of Biology, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
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Hiroshi TOKUMITSU
Department of Signal Transduction Sciences, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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Ryoji KOBAYASHI
Department of Signal Transduction Sciences, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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Abstract

The NCS (neuronal calcium sensor) proteins, including neurocalcins, recoverins and visinin-like proteins are members of a family of Ca2+-sensitive regulators, each with three Ca2+-binding EF-hand motifs. In plants, lily CCaMK [chimaeric Ca2+/CaM (calmodulin)-dependent protein kinase] and its PpCaMK (Physcomitrella patens CCaMK) homologue are characterized by a visinin-like domain with three EF-hands. In the present study, in an effort to discover NCS antagonists, we screened a total of 43 compounds using Ca2+-dependent drug affinity chromatography and found that the insulinotropic agent repaglinide targets the NCS protein family. Repaglinide was found to bind to NCS proteins, but not to CaM or S100 proteins, in a Ca2+-dependent manner. Furthermore, the drug antagonized the inhibitory action of recoverin in a rhodopsin kinase assay with IC50 values of 400 μM. Moreover, repaglinide tightly bound to the visinin-like domain of CCaMK and PpCaMK in a Ca2+-dependent manner and antagonized the regulatory function of the domain with IC50 values of 55 and 4 μM for CCaMK and PpCaMK respectively. Although both repaglinide and a potent insulin secretagogue, namely glibenclamide, blocked KATP channels with similar potency, glibenclamide had no antagonizing effect on the Ca2+-stimulated CCaMK and PpCaMK autophosphorylation, mediated by their visinin-like domain. In addition, a typical CaM antagonist, trifluoperazine, had no effect on the CCaMK and PpCaMK autophosphorylation. Repaglinide appears to be the first antagonist of NCS proteins and visinin-like domain-bearing enzymes. It may serve as a useful tool for evaluating the physiological functions of the NCS protein family. In addition, since repaglinide selectively targets NCS proteins among the EF-hand Ca2+-binding proteins, it is a potential lead compound for the development of more potent NCS antagonists.

  • calcium-binding protein
  • EF-hand motif
  • visinin-like domain

Footnotes

  • Abbreviations used: CaM, calmodulin; CaMKII, Ca2+/CaM-dependent protein kinase II; CCaMK, chimaeric Ca2+/CaM-dependent protein kinase; DMF, N,N′-dimethylformamide; EAH, epoxy-aminohexyl; NCS, neuronal calcium sensor; PpCaMK, Physcomitrella patens CCaMK; SUR, sulphonylurea receptor; W-7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide; W-66, N-(2-aminoethyl)-N-[2-(4-chlorocinnamylamino)ethyl]-5-isoquinolinesulphonamide; WT, wild-type.

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October 2003

Volume: 375 Issue: 1

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Neuronal calcium sensor proteins are direct targets of the insulinotropic agent repaglinide
Miki OKADA, Daisuke TAKEZAWA, Shuji TACHIBANAKI, Satoru KAWAMURA, Hiroshi TOKUMITSU, Ryoji KOBAYASHI
Biochemical Journal Oct 2003, 375 (1) 87-97; DOI: 10.1042/bj20030376
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Neuronal calcium sensor proteins are direct targets of the insulinotropic agent repaglinide
Miki OKADA, Daisuke TAKEZAWA, Shuji TACHIBANAKI, Satoru KAWAMURA, Hiroshi TOKUMITSU, Ryoji KOBAYASHI
Biochemical Journal Oct 2003, 375 (1) 87-97; DOI: 10.1042/bj20030376

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Keywords

calcium-binding protein
EF-hand motif
visinin-like domain

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