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Extracellular ATP induces oscillations of intracellular Ca(2+) and membrane potential and promotes transcription of IL-6 in macrophages

By Peter J. Hanley, Boris Musset, Vijay Renigunta, Sven H. Limberg, Alexander H. Dalpke, Rainer Sus, Klaus M. Heeg, Regina Preisig-Müller and Jürgen Daut

Abstract

The effects of low concentrations of extracellular ATP on cytosolic Ca(2+), membrane potential, and transcription of IL-6 were studied in monocyte-derived human macrophages. During inflammation or infection many cells secrete ATP. We show here that application of 10 μM ATP or 10 μM UTP induces oscillations in cytosolic Ca(2+) with a frequency of ≈12 min(-1) and oscillations in membrane potential. RT-PCR analysis showed expression of P2Y(1), P2Y(2), P2Y(11), P2X(1), P2X(4), and P2X(7) receptors, large-conductance (KCNMA1 and KCNMB1–4), and intermediate-conductance (KCNN4) Ca(2+)-activated K(+) channels. The Ca(2+)oscillations were unchanged after removal of extracellular Ca(2+), indicating that they were mainly due to movements of Ca(2+) between intracellular compartments. Comparison of the effects of different nucleotides suggests that the Ca(2+) oscillations were elicited by activation of P2Y(2) receptors coupled to phospholipase C. Patch–clamp experiments showed that ATP induced a transient depolarization, probably mediated by activation of P2X(4) receptors, followed by membrane potential oscillations due to opening of Ca(2+)-activated K(+) channels. We also found that 10 μM ATPγS increased transcription of IL-6 ≈40-fold within 2 h. This effect was abolished by blockade of P2Y receptors with 100 μM suramin. Our results suggest that ATP released from inflamed, damaged, or metabolically impaired cells represents a “danger signal” that plays a major role in activating the innate immune system

Topics: Biological Sciences
Publisher: National Academy of Sciences
Year: 2004
DOI identifier: 10.1073/pnas.0400733101
OAI identifier: oai:pubmedcentral.nih.gov:439002
Provided by: PubMed Central
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