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Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Iβ

Author

Listed:
  • Jens Schlossmann

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München)

  • Aldo Ammendola

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München)

  • Keith Ashman

    (Protein and Peptide Group, EMBL)

  • Xiangang Zong

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München)

  • Andrea Huber

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München)

  • Gitte Neubauer

    (Protein and Peptide Group, EMBL)

  • Ge-Xin Wang

    (Protein and Peptide Group, EMBL
    Universitäts-Krankenhaus Eppendorf)

  • Hans-Dieter Allescher

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München
    II. Medizinische Klinik und Poliklinik der TU München)

  • Michael Korth

    (Protein and Peptide Group, EMBL
    Universitäts-Krankenhaus Eppendorf)

  • Matthias Wilm

    (Protein and Peptide Group, EMBL)

  • Franz Hofmann

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München)

  • Peter Ruth

    (Institut für Pharmakologie und Toxikologie der Technischen Universität München)

Abstract

Calcium release from the endoplasmic reticulum controls a number of cellular processes, including proliferation and contraction of smooth muscle and other cells1,2. Calcium release from inositol 1,4,5-trisphosphate (IP3)-sensitive stores is negatively regulated by binding of calmodulin to the IP3 receptor (IP3R)3,4 and the NO/cGMP/cGMP kinase I (cGKI) signalling pathway5,6. Activation of cGKI decreases IP3-stimulated elevations in intracellular calcium7, induces smooth muscle relaxation8 and contributes to the antiproliferative9 and pro-apoptotic effects of NO/cGMP10. Here we show that, in microsomal smooth muscle membranes, cGKIβ phosphorylated the IP3R and cGKIβ, and a protein of relative molecular mass 125,000 which we now identify as the IP3R-associated cGMP kinase substrate (IRAG). These proteins were co-immunoprecipitated by antibodies directed against cGKI, IP3R or IRAG. IRAG was found in many tissues including aorta, trachea and uterus, and was localized perinuclearly after heterologous expression in COS-7 cells. Bradykinin-stimulated calcium release was not affected by the expression of either IRAG or cGKIβ, which we tested in the absence and presence of cGMP. However, calcium release was inhibited after co-expression of IRAG and cGKIβ in the presence of cGMP. These results identify IRAG as an essential NO/cGKI-dependent regulator of IP3-induced calcium release.

Suggested Citation

  • Jens Schlossmann & Aldo Ammendola & Keith Ashman & Xiangang Zong & Andrea Huber & Gitte Neubauer & Ge-Xin Wang & Hans-Dieter Allescher & Michael Korth & Matthias Wilm & Franz Hofmann & Peter Ruth, 2000. "Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Iβ," Nature, Nature, vol. 404(6774), pages 197-201, March.
    • Handle: RePEc:nat:nature:v:404:y:2000:i:6774:d:10.1038_35004606
    DOI: 10.1038/35004606
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    1. Lei Ying & Luyao Wang & Kaiwen Guo & Yushu Hou & Na Li & Shuyi Wang & Xingfeng Liu & Qijin Zhao & Jie Zhou & Longwei Zhao & Jianlou Niu & Chuchu Chen & Lintao Song & Shaocong Hou & Lijuan Kong & Xiaok, 2021. "Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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