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Am J Physiol Cell Physiol (September 24, 2003). doi:10.1152/ajpcell.00331.2003
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Submitted on August 1, 2003
Accepted on September 9, 2003

HYDROGEN PEROXIDE AND ADP-RIBOSE INDUCE TRPM2-MEDIATED CALCIUM INFLUX AND CATION CURRENTS IN MICROGLIA

Robert Kraft1, Christian Grimm2, Karin Grosse1, Anja Hoffmann3, Sophie Sauerbruch1, Helmut Kettenmann3, Gunter Schultz1, and Christian Harteneck1*

1 Institut fuer Pharmakologie, Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
2 Institut fuer Pharmakologie, Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; Fachbereich Biologie, Chemie, Pharmazie, Freie Universitaet Berlin, Berlin, Germany
3 ; Zellulaere Neurowissenschaften, Max-Delbruck-Centrum fuer Molekulare Medizin, Berlin, Germany

* To whom correspondence should be addressed. E-mail: hartenek{at}zedat.fu-berlin.de.

Microglial cells are the host macrophages in the CNS and respond to brain injury and various neurological diseases. In this process, microglial cells undergo multiple morphological and functional changes from the resting cell towards a fully activated, phagocyting tissue macrophage. In culture, bacterial lipopolysaccharide (LPS) is a frequently used tool to induce this activation. 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 to 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 non-selective 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 of TRPM2 in the calcium signaling of activated microglia.




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