Zinc ions are endogenous modulators of neurotransmitter-stimulated capacitative Ca2+ entry in both cultured and in situ mouse astrocytes

Wolfgang Kresse, Israel Sekler, Anja Hoffmann, Oliver Peters, Christiane Nolte, Arie Moran, Helmut Kettenmann

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Astrocytes express a variety of metabotropic receptors and their activation leads to a biphasic Ca2+ response due to Ca2+ release from intracellular stores and subsequent capacitative Ca2+ entry. We performed Ca2+ imaging with Fura-2 on cultured mouse astrocytes and showed that extracellular zinc reversibly blocks the capacitative Ca 2+ entry following application of the metabotropic ligands ATP, glutamate and endothelin-1. Zinc blocked the plateau phase of the ligand-triggered Ca2+ responses. When ligands were repetitively applied in the presence of zinc the calcium responses progressively decayed and even disappeared, indicating that capacitative Ca2+ entry is required to refill the stores. Zinc inhibited the capacitative Ca2+ entry with a Ki of ≈6 μM, which is well within the physiological concentration range of zinc found in the brain. Application of the reducing agent DTT prevented the blocking effect by zinc ions but not the inhibition elicited by the nonphysiological metal ions Gd3+ and La3+, indicating that zinc has a distinct binding site. To monitor the capacitative Ca2+ entry in astrocytes in situ and to determine the effect of zinc on this pathway we utilized X-rhod-1 imaging in hippocampal slices of a transgenic mouse line with green fluorescent astrocytes. Zinc affected the repetitive metabotropic Ca2+ response in the following fashion: (i) after depleting stores in Ca2+-free solution, re-addition of Ca 2+ led to an influx of Ca2+ via a zinc-sensitive Ca 2+ entry route; (ii) with repetitive application of metabotropic ligands, Ca2+ responses became smaller and even disappeared in the presence of zinc. We conclude that zinc, which is coreleased from glutamatergic synaptic vesicles upon neuronal activity, has a major impact on shaping the astrocytic calcium responses.

Original languageEnglish
Pages (from-to)1626-1634
Number of pages9
JournalEuropean Journal of Neuroscience
Volume21
Issue number6
DOIs
StatePublished - 1 Mar 2005

Keywords

  • ATP
  • Astrocytes
  • Brain slice
  • Ca signalling
  • Ca stores
  • Metabotropic glutamate receptors
  • SOCC
  • Zinc

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