title: Inhibition of antigen receptor-dependent Ca(2+) signals and NF-AT activation by P2X7 receptors in human B lymphocytes.
abstract: One of the first intracellular signals after antigen binding by the antigen receptor of B lymphocytes is the increased intracellular Ca(2+) concentration ([Ca(2+)]i), which is followed by several intracellular signaling events like the nuclear translocation of the transcription factor NF-AT controlling the fate of B lymphocytes after their activation. Extracellular ATP, which is released from cells under several pathological conditions, is considered a danger-associated signal serving as an immunomodulator. We investigated the interaction of antigen receptor (BCR) and P2X7 receptor (P2X7R) activation on [Ca(2+)]i signaling and on nuclear translocation of the transcription factor NF-AT in human B lymphocytes. Although the P2X7R is an ATP-gated Ca(2+)-permeable ion channel, P2X7R activation inhibits the BCR-mediated [Ca(2+)]i responses. This effect is mimicked by cell membrane depolarization induced by an increase in the extracellular K(+) concentration or by application of the Na(+) ionophore gramicidin, but is abolished by stabilization of the membrane potential using the K(+) ionophore valinomycin, by extracellular Mg(2+), which is known to inhibit P2X7R-dependent effects, or by replacing Na(+) by the less P2X7R-permeable Tris(+) ion. Furthermore, P2X7R activation by ATP inhibits the BCR-dependent translocation of the transcription factor NF-ATc1 to the nucleus. We therefore conclude that extracellular ATP via the P2X7R mediates inhibitory effects on B cell activation. This may be of relevance for understanding of the activation of the BCR under pathological conditions and for the development of therapeutic strategies targeting human B lymphocytes or P2X7 receptors.
authors: Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle, Magdeburger Straße 6, D-06097 Halle (Saale), Germany.
authors: Anja
authors: A
authors: Pippel
authors: Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle, Magdeburger Straße 6, D-06097 Halle (Saale), Germany.
authors: Björn
authors: B
authors: Beßler
authors: Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle, Magdeburger Straße 6, D-06097 Halle (Saale), Germany.
authors: Manuela
authors: M
authors: Klapperstück
authors: Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle, Magdeburger Straße 6, D-06097 Halle (Saale), Germany. Electronic address: fritz.markwardt@medizin.uni-halle.de.
authors: Fritz
authors: F
authors: Markwardt
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D020013:Calcium Signaling / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D006096:Gramicidin / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation; D008274:Magnesium / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D020239:Receptor Cross-Talk; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D014634:Valinomycin / Q000494:pharmacology
chemical_list: D050778:NFATC Transcription Factors; D009467:Neuromuscular Depolarizing Agents; D011947:Receptors, Antigen, B-Cell; D058486:Receptors, Purinergic P2X7; D006096:Gramicidin; D014634:Valinomycin; D000255:Adenosine Triphosphate; D008274:Magnesium; D011188:Potassium
keywords: B lymphocytes; Intracellular Ca(2+) concentration; NF-AT; P2X7 receptor; Store-operated Ca(2+) channel