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First published online 30 March 2004
doi: 10.1242/jcs.01063

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Amplification and propagation of pacemaker Ca²⁺ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells

Svenja Kunerth¹, Matthias F. Langhorst¹, Nadine Schwarzmann^1,*, Xianfeng Gu², Lijun Huang², Zhenjun Yang², Liangren Zhang², Steven J. Mills³, Li-he Zhang², Barry V.L. Potter³ and Andreas H. Guse^1,

¹ University Hospital Hamburg-Eppendorf, Center for Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Martinistr. 52, 20246 Hamburg, Germany
² National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xue Yuan Road, Beijing 100083, China
³ Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK

Author for correspondence (e-mail: guse{at}uke.uni-hamburg.de)

Accepted 17 December 2003

Ligation of the T-cell receptor/CD3 complex results in global Ca²⁺ signals that are essential for T-cell activation. We have recently reported that these global Ca²⁺ signals are preceded by localized pacemaker Ca²⁺ signals. Here, we demonstrate for the first time for human T cells that an increase in signal frequency of subcellular pacemaker Ca²⁺ signals at sites close to the plasma membrane, in the cytosol and in the nucleus depends on the type 3 ryanodine receptor (RyR) and its modulation by cyclic ADP-ribose. The spatial distribution of D-myo-inositol 1,4,5-trisphosphate receptors and RyRs indicates a concerted action of both of these receptors/Ca²⁺ channels in the generation of initial pacemaker signals localized close to the plasma membrane. Inhibition or knockdown of RyRs resulted in significant decreases in (1) the frequency of initial pacemaker signals localized close to the plasma membrane, and (2) the frequency of localized pacemaker Ca²⁺ signals in the inner cytosol. Moreover, upon microinjection of cyclic ADP-ribose or upon extracellular addition of its novel membrane-permeant mimic N-1-ethoxymethyl-substituted cyclic inosine diphosphoribose, similarly decreased Ca²⁺ signals were observed in both type 3 RyR-knockdown cells and in control cells microinjected with the RyR antagonist Ruthenium Red. Taken together, our results show that, under physiological conditions in human T cells, RyRs play crucial roles in the local amplification and the spatiotemporal development of subcellular Ca²⁺ pacemaker signals.

Key words: Ca²⁺ signaling, Ryanodine receptor, Cyclic ADP-ribose, T cell, D-myo-inositol 1,4,5-trisphosphate receptor

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