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Am J Physiol Cell Physiol 286: C129-C137, 2004. First published September 24, 2003; doi:10.1152/ajpcell.00331.2003
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia

Robert Kraft,1 Christian Grimm ,1,2 Karin Grosse,1 Anja Hoffmann,3 Sophie Sauerbruch,1 Helmut Kettenmann,3 Günter Schultz,1 and Christian Harteneck1

1Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, D-14195 Berlin; 2Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin, 14195 Berlin; and 3Zelluläre Neurowissenschaften, Max-Delbrück-Centrum für Molekulare Medizin, D-13092 Berlin, Germany

Submitted 1 August 2003 ; accepted in final form 9 September 2003

Microglial cells are the host macrophages in the central nervous system and respond to brain injury and various neurological diseases. In this process, microglial cells undergo multiple morphological and functional changes from the resting cell toward a fully activated, phagocyting tissue macrophage. In culture, bacterial lipopolysaccharide (LPS) is a frequently used tool to induce this activation. By using calcium-imaging and patch-clamp techniques, we investigated the effect of hydrogen peroxide (H2O2), which is released by macrophagic cells themselves, on the intracellular calcium concentration and ion currents in cultured rat microglia. Application of 0.1–5 mM H2O2 for several minutes induced small responses in untreated cells but a large calcium influx and cation current in LPS-treated cells. In both untreated and LPS-treated microglia, internal perfusion of ADP-ribose (ADPR) via the patch pipette elicited large cation currents. Both stimuli, H2O2 and ADPR, have been reported to activate the recently cloned nonselective cation channel TRPM2. RT-PCR analysis from cultured rat glial and neuronal cells confirmed a strong expression of TRPM2 in rat microglia but not in astrocytes and cerebellar granule cells. In situ hybridizations from mouse brain showed a distribution of TRPM2, which is compatible with the expression in microglial cells. In conclusion, we describe here a novel calcium influx pathway in microglia coupled to hydrogen peroxide and ADPR and provide evidence that this pathway involves TRPM2. The increased sensitivity to H2O2 in LPS-stimulated cells suggests a role for TRPM2 in the calcium signaling of activated microglia.

nonselective cation channel; transient receptor potential channel; H2O2; activated microglia


Address for reprint requests and other correspondence: C. Harteneck, Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 69-73, 14195 Berlin, Germany (E-mail: hartenek{at}zedat.fu-berlin.de).




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