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P2X7 RECEPTOR TRIGGERS LYSOSOMAL LEAKAGE THROUGH CALCIUM MOBILIZATION IN A MECHANISM DEPENDENT ON PANNEXIN-1 HEMICHANNELS
Receptor P2
Catepsinas
ATP extracelular
Permeabilização lisossomal
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Abstract
The P2X7 receptor is a critical purinergic receptor in immune cells. Its activation was
associated with cathepsin release into macrophage cytosol, suggesting its involvement in
lysosomal membrane permeabilization (LMP) and leakage. Nevertheless, the mechanisms
by which P2X7 receptor activation induces LMP and leakage are unclear. This study
investigated cellular mechanisms associated with endosomal and lysosomal leakage
triggered by P2X7 receptor activation. We found that ATP at 500 mM and 5 mM (but not
50 mM) induced LMP in non-stimulated peritoneal macrophages. This effect was not
observed in P2X7-deficient or A740003-pretreated macrophages. We found that the
P2X7 receptor and pannexin-1 channels mediate calcium influx that might be important
for activating specific ion channels (TRPM2 and two-pore channels) on the membranes of
late endosomes and lysosomes leading to LMP leakage and consequent cathepsin
release. These findings suggest the critical role of the P2X7 receptor in inflammatory and
infectious diseases via lysosomal dysfunction.
Keywords in Portuguese
LisossomosReceptor P2
Catepsinas
ATP extracelular
Permeabilização lisossomal
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