Expression of the P2X7 receptor increases the Ca2+ content of the endoplasmic reticulum, activates NFATc1, and protects from apoptosis.
The P2X(7) receptor is known for the cytotoxic activity because of its ability to cause opening of non-selective pores in the plasma membrane and activate apoptotic caspases. A key factor of P2X(7)-dependent cytotoxicity is the massive intracellular Ca(2+) increase triggered by its activation. Here we show that P2X(7) transfection increased the ability of the endoplasmic reticulum to accumulate, store, and release Ca(2+). This caused a larger agonist-stimulated increase in cytosol and mitochondrial Ca(2+) in P2X(7) transfectants than in mock transfected cells. P2X(7) transfectants survived and even proliferated in serum-free conditions and were resistant to apoptosis triggered by ceramide, staurosporin, or intracellular Zn(2+) chelation. Finally, the nuclear factor of activated T cells complex 1 (NFATc1) was strongly activated in the P2X(7) transfectants. These observations support our previous finding that the P2X(7) receptor under tonic conditions of stimulation, i.e. those observed in response to basal ATP release, has an anti-apoptotic or even growth promoting rather than cytotoxic activity.
Adinolfi
Elena
E
Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, via Borsari 46, 44100 Ferrara, Italy. elena.adinolfi@unife.it
Callegari
Maria Giulia
MG
Cirillo
Maria
M
Pinton
Paolo
P
Giorgi
Carlotta
C
Cavagna
Dario
D
Rizzuto
Rosario
R
Di Virgilio
Francesco
F
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis* / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D014162:Transfection; D015032:Zinc / Q000494:pharmacology
D002614:Chelating Agents; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D015032:Zinc; D002118:Calcium