Apoptosis of murine thymocytes induced by extracellular ATP is dose- and cytosolic pH-dependent

P. éter V. Nagy, Tamás Fehér, Sabina Morga, J. ános Matkó

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Thymocytes from young Balb/C mice responded to low extracellular ATP (ATPec) doses (≤0.3 mM) with a rapid intracellular acidification (mean pH: ca. 0.3 pH unit) that was inhibited by the Ca2+ channel blocker verapamil, or by suramin (50 μM) and TNP-ATP (40 μM), potent P2x (and P2y) purinoreceptor antagonists. ATPec also triggered a remarkable DNA fragmentation and cell shrinkage detectable only at these low doses. DNA fragmentation gradually disappears with increasing [ATPec] above 0.5 mM, with a concomitant dominance of cytosolic alkalinization of the cells. Suramin and TNP-ATP also blocked the ATPec-triggered DNA fragmentation efficiently. oATP, inhibitor of P2z nonspecific ATP-gated membrane pores, and 2 mM extracellular Mg2+ did not influence either the cytosolic acidification or the DNA fragmentation, but almost completely abolished the intracellular alkalinization characteristic of P2z receptor activation at high ATPec doses. Antagonist-sensitivity of the ATPec-induced membrane potential responses indicates that hyperpolarization is associated with intracellular acidification, while rapid depolarization is linked to alkalinization. These data together indicate that the Ca2+-dependent hyperpolarization and cytosolic acidification triggered by low ATPec doses are essential early signals in apoptosis of murine thymocytes and are likely mediated by P2x1 type ATP-gated ion channels. Subset specificity of the early purinergic signals suggests that the double positive thymocytes are most sensitive to ATPec showing both P2z and P2x receptor activation characteristics, the double negative thymocytes preferentially show P2z-type, while single positive (CD4-CD8+ or CD4+CD8-) thymocytes respond mostly by weaker P2x-type changes, indicating that ATPec, similarly to adenosine may serve as a potential regulator of cell death and differentiation in the thymus.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalImmunology letters
Volume72
Issue number1
DOIs
Publication statusPublished - Apr 3 2000

Keywords

  • Cytosolic pH
  • DNA fragmentation
  • P2 purinoreceptors
  • Plasma membrane potential
  • Thymocyte apoptosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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