Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca2+ signals between lysosomes and the endoplasmic reticulum
Yu Yuan,
Vikas Arige,
Ryo Saito,
Qianru Mu,
Gabriela C. Brailoiu,
Gustavo J.S. Pereira,
Stephen R. Bolsover,
Marco Keller,
Franz Bracher,
Christian Grimm,
Eugen Brailoiu,
Jonathan S. Marchant,
David I. Yule,
Sandip Patel
Affiliations
Yu Yuan
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK
Vikas Arige
Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA
Ryo Saito
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK; Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
Qianru Mu
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK
Gabriela C. Brailoiu
Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, 901 Walnut Street, Philadelphia, PA 19107, USA
Gustavo J.S. Pereira
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK; Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo 04044-020, Brazil
Stephen R. Bolsover
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK
Marco Keller
Department of Pharmacy—Center for Drug Research, Ludwig-Maximilian University, Butenandtstrasse 5-13, 81377 Munich, Germany
Franz Bracher
Department of Pharmacy—Center for Drug Research, Ludwig-Maximilian University, Butenandtstrasse 5-13, 81377 Munich, Germany
Christian Grimm
Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilian University, Nussbaumstrasse 26, 80336 Munich, Germany; Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany
Eugen Brailoiu
Department of Neural Sciences and Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Jonathan S. Marchant
Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
David I. Yule
Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA; Corresponding author
Sandip Patel
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK; Corresponding author
Summary: Lysosomes and the endoplasmic reticulum (ER) are Ca2+ stores mobilized by the second messengers NAADP and IP3, respectively. Here, we establish Ca2+ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca2+. Cell-wide Ca2+ signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca2+ despite their lysosomal origin. Knockout of ER IP3 receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca2+ imaging reveals elementary events upon TPC2 opening and signals coupled to IP3 receptors. Biasing TPC2 activation to a Ca2+-permeable state sensitizes local Ca2+ signals to IP3. This increases the potency of a physiological agonist to evoke global Ca2+ signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca2+ release from physically separated stores is coordinated.
