Sodium channels enable fast electrical signaling and regulate phagocytosis in the retinal pigment epithelium

Voltage-gated sodium (Na_v) channels have traditionally been considered a trademark of excitable cells. However, recent studies have shown the presence of Na_v channels in several non-excitable cells, such as astrocytes and macrophages, demonstrating that the roles of these channels are more diverse than was previously thought. Despite the earlier discoveries, the presence of Na_v channel-mediated currents in the cells of retinal pigment epithelium (RPE) has been dismissed as a cell culture artifact. We challenge this notion by investigating the presence and possible role of Na_v channels in RPE both ex vivo and in vitro.

Our work demonstrates that several subtypes of Na_v channels are found in human embryonic stem cell (hESC)-derived and mouse RPE, most prominently subtypes Na_v1.4, Na_v1.6, and Na_v1.8. Whole cell patch clamp recordings from the hESC-derived RPE monolayers showed that the current was inhibited by TTX and QX-314 and was sensitive to the selective blockers of the main Na_v subtypes. Importantly, we show that the Na_v channels are involved in photoreceptor outer segment phagocytosis since blocking their activity significantly reduces the efficiency of particle internalization. Consistent with this role, our electron microscopy results and immunocytochemical analysis show that Na_v1.4 and Na_v1.8 accumulate on phagosomes and that pharmacological inhibition of Na_v channels as well as silencing the expression of Na_v1.4 with shRNA impairs the phagocytosis process.

Taken together, our study shows that Na_v channels are present in RPE, giving this tissue the capacity of fast electrical signaling. The channels are critical for the physiology of RPE with an important role in photoreceptor outer segment phagocytosis.