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The role of a purinergic P 2z receptor in calcium‐dependent cell killing of isolated rat hepatocytes by extracellular adenosine triphosphate
Author(s) -
Zoetewij J P,
van de Water B,
de Bont H J,
Nagelkerke J F
Publication year - 1996
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510230429
Subject(s) - extracellular , purinergic receptor , intracellular , agonist , adenosine triphosphate , cytolysis , adenosine , receptor , calcium in biology , biophysics , biology , biochemistry , chemistry , microbiology and biotechnology , cytotoxicity , in vitro
Extracellular adenosine triphosphate (ATP o ) (0.4 mmol/L), a P 2 ‐purinergic receptor agonist, induces cytolysis in several cell types including isolated rat hepatocytes. In this study, we investigated the P 2 ‐receptor involved in ATP o ‐induced, Ca 2+ ‐dependent cytotoxicity in hepatocytes. Pretreatment of hepatocytes with oxidized ATP, a P 2z ‐receptor antagonist, or complexation of ATP 4− (the agonist for the P 2z ‐receptor) with an excess of Mg 2+ , prevented ATP o ‐induced cell death. Both protective treatments also prevented the development of a sustained high intracellular Ca 2+ concentration as well as the subsequent accumulation of inorganic phosphate (Pi). The P 2z ‐receptor agonist 3′‐O‐'(4‐benzoylbenzoyl)‐ATP (BzATP) was twofold more potent than ATP in eliciting cytolysis, which was preceded by a sustained high intracellular Ca 2+ concentration; pretreatment with oxidized ATP prevented both the increase in the intracellular Ca 2+ concentration and cell death. Prevention of ATP o ‐induced cell death, as well as the increases in the intracellular Ca 2+ concentration and inorganic phosphate (Pi) was also achieved by decreasing the pH o to 6.9. Together the findings indicate that Ca 2+ ‐dependent cell killing by extracellular ATP in hepatocytes is mediated by a P 2z ‐receptor. The cytolytic effects correlated specifically with a secondary “late” increase in the intracellular Ca 2+ concentration.