Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth.
P2X7 is a bifunctional receptor (P2X7R) for extracellular ATP that, depending on the level of activation, forms a cation-selective channel or a large conductance nonselective pore. The P2X7R has a strong proapoptotic activity but can also support growth. Here, we describe the mechanism involved in growth stimulation. Transfection of P2X7R increases resting mitochondrial potential (delta psi(mt)), basal mitochondrial Ca2+ ([Ca2+]mt), intracellular ATP content, and confers ability to grow in the absence of serum. These changes require a full pore-forming function, because they are abolished in cells transfected with a mutated P2X7R that retains channel activity but cannot form the nonselective pore, and depend on an autocrine/paracrine tonic stimulation by secreted ATP. On the other hand, sustained stimulation of P2X7R causes a delta psi(mt) drop, a large increase in [Ca2+]mt, mitochondrial fragmentation, and cell death. These findings reveal a hitherto undescribed mechanism for growth stimulation by a plasma membrane pore.
Adinolfi
Elena
E
Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, 44100 Ferrara, Italy.
Callegari
Maria Giulia
MG
Ferrari
Davide
D
Bolognesi
Chiara
C
Minelli
Mattia
M
Wieckowski
Mariusz R
MR
Pinton
Paolo
P
Rizzuto
Rosario
R
Di Virgilio
Francesco
F
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D007477:Ions; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D013997:Time Factors; D014162:Transfection
D016895:Culture Media, Serum-Free; D007477:Ions; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D002118:Calcium