Basal Activation of the P2X₇ ATP Receptor Elevates Mitochondrial Calcium and Potential, Increases Cellular ATP Levels, and Promotes Serum-independent Growth

Abstract

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.

P2X7: a growth-promoting receptor—implications for cancer

“…In agreement with our previous findings in T lymphocytes, the mere P2X 7 transfection, in the absence of stimulation with exogenous ATP, conferred a strong growth advantage but only in the absence of serum [5]. We then extended these observations to human chronic lymphocytic leukemia (CLL) cells.…”

“…We then extended these observations to human chronic lymphocytic leukemia (CLL) cells. Peripheral lymphocytes from these patients turned out to have a several-fold higher P2X 7 expression level compared to lymphocytes isolated from healthy subjects and larger increases in cytoplasmic Ca 2+ in response to P2X 7 agonists [6]. These concordant findings instigated a thorough examination of the biochemical intracellular changes involved.…”

“…cell lines expressing the P2X 7 receptor (at the time known as P2Z) [1,2]. Accordingly, it was not surprising that blockade of P2X 7 significantly reduced spontaneous cell death in cultures of selected cell lines [3]. Problems started when we found that proliferation of ex vivo cultures of human T lymphocytes far from being inhibited was in fact enhanced by pharmacological stimulation of a nucleotide receptor/channel with properties very similar to P2X 7 [4].…”

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

“…In fact, among all cancer types tested, cervical cancer is the only exception to our knowledge with a decreased expression of P2X 7 R in cancer cells (Li et al, 2006). Contrarily to initial assumptions, P2X 7 R were reported to have anti-apoptotic effects (Deli et al, 2007) and even to promote cell growth (Adinolfi et al, 2005;Raffaghello et al, 2006;Di Virgilio et al, 2009) in some cancer cells. All these studies mainly focused on the regulation of cell proliferation/apoptosis and other important parameters such as cancer cell invasiveness were not assessed.…”

“…One possible explanation for this could be the tonic release of ATP by cancer cells responsible for autocrine/paracrine regulations. Indeed, P2X 7 R have already been demonstrated to be responsible for trophic activities on different cell types, including cancer cells, in the absence of ATP stimulation (Adinolfi et al, 2005(Adinolfi et al, , 2010Di Virgilio et al, 2009). Alternatively, one other hypothesis could be a basal, channel-independent, activity of the receptor in the complete absence of any purinergic stimulation.…”