A role for P2X4 receptors in lysosome function

P2X4 is an ATP-gated cation channel that is widely expressed in most tissues in the body and at especially high levels within immune, endothelial, and epithelial cells. This channel plays a role in the secretion of inflammatory mediators, including brain-derived neurotrophic factor and prostaglandin E2, and as a regulator of cardiac contractility and vascular remodeling (Stokes et al., 2017; Suurväli et al., 2017). Within the P2X family, P2X4 has a unique subcellular distribution that is predominantly intracellular, within endolysosomal compartments (Bobanovic et al., 2002; Qureshi et al., 2007). This unusual distribution has sparked a debate about whether it might function at endolysosomal membranes in addition to its role at the plasma membrane. Patch-clamp recordings of ATP-evoked currents from enlarged vacuolar lysosomes have supported this view and revealed that lysosomal P2X4 receptors are under the dual regulation of intraluminal ATP and pH (Huang et al., 2014). The evidence to date suggests that P2X4 is one of several highly Ca2+-permeable lysosomal channels that control lysosomal Ca2+ fluxes and lysosome membrane trafficking events (Cao et al., 2015). Much of this evidence is based, however, on pharmacological manipulation of lysosome pH. In this issue of the Journal of General Physiology, Fois et al. provide a clearer description of the physiological role of lysosomal P2X4 receptors during the secretion of surfactant from alveolar type II (ATII) epithelial cells.