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Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src

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Abstract

Apolipoprotein CIII (ApoCIII) not only serves as an inhibitor of triglyceride hydrolysis but also participates in diabetes-related pathological events such as hyperactivation of voltage-gated Ca2+ (CaV) channels in the pancreatic β cell. However, nothing is known about the molecular mechanisms whereby ApoCIII hyperactivates β cell CaV channels. We now demonstrate that ApoCIII increased CaV1 channel open probability and density. ApoCIII enhanced whole-cell Ca2+ currents and the CaV1 channel blocker nimodipine completely abrogated this enhancement. The effect of ApoCIII was not influenced by individual inhibition of PKA, PKC, or Src. However, combined inhibition of PKA, PKC, and Src counteracted the effect of ApoCIII, similar results obtained by coinhibition of PKA and Src. Moreover, knockdown of β1 integrin or scavenger receptor class B type I (SR-BI) prevented ApoCIII from hyperactivating β cell CaV channels. These data reveal that ApoCIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src.

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Abbreviations

ApoCIII:

Apolipoprotein CIII

CaV :

Voltage-gated Ca2+

SR-BI:

Scavenger receptor class B type I

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Acknowledgments

This work was supported by grants from Berth von Kantzow’s Foundation, Diabetes Research and Wellness Foundation, EuroDia (FP6-518153), the Family Erling-Persson Foundation, Fredrik and Ingrid Thuring’s Foundation, Funds of Karolinska Institutet, the Knut and Alice Wallenberg Foundation, Magn. Bergvall’s Foundation, Novo Nordisk Foundation, Skandia Insurance Company, Ltd., the Stichting af Jochnick Foundation, Strategic Research Program in Diabetes at Karolinska Institutet, the Swedish Alzheimer Association, the Swedish Diabetes Association, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Society of Medicine, Torsten and Ragnar Söderberg Foundation, VIBRANT (FP7-228933-2) and Åke Wiberg’s Foundation. P.-O. Berggren is founder of the Biotech Company BioCrine AB and is also a member of the board of this company. S.-N.Yang is a consultant to BioCrine AB. BioCrine AB is developing ApoCIII as a novel druggable target for the treatment of diabetes.

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Authors and Affiliations

  1. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76, Stockholm, Sweden

    Yue Shi, Guang Yang, Jia Yu, Lina Yu, Lisa Juntti-Berggren, Per-Olof Berggren & Shao-Nian Yang

  2. Jilin Academy of Traditional Chinese Medicine, Changchun, 130021, China

    Guang Yang

  3. Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA, 98195-7280, USA

    Ruth Westenbroek & William A. Catterall

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  1. Yue Shi
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  2. Guang Yang
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  3. Jia Yu
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  4. Lina Yu
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  5. Ruth Westenbroek
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  6. William A. Catterall
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  7. Lisa Juntti-Berggren
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  8. Per-Olof Berggren
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  9. Shao-Nian Yang
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Correspondence to Per-Olof Berggren or Shao-Nian Yang.

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Yue Shi and Guang Yang have contributed equally to this work.

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Shi, Y., Yang, G., Yu, J. et al. Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src. Cell. Mol. Life Sci. 71, 1289–1303 (2014). https://doi.org/10.1007/s00018-013-1442-x

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