The Na⁺/Ca²⁺, K⁺ exchanger NCKX4 is required for efficient cone-mediated vision

Calcium (Ca²⁺) plays an important role in the function and health of neurons. In vertebrate cone photoreceptors, Ca²⁺ controls photoresponse sensitivity, kinetics, and light adaptation. Despite the critical role of Ca²⁺ in supporting the function and survival of cones, the mechanism for its extrusion from cone outer segments is not well understood. Here, we show that the Na⁺/Ca²⁺, K⁺ exchanger NCKX4 is expressed in zebrafish, mouse, and primate cones. Functional analysis of NCKX4-deficient mouse cones revealed that this exchanger is essential for the wide operating range and high temporal resolution of cone-mediated vision. We show that NCKX4 shapes the cone photoresponse together with the cone-specific NCKX2: NCKX4 acts early to limit response amplitude, while NCKX2 acts late to further accelerate response recovery. The regulation of Ca²⁺ by NCKX4 in cones is a novel mechanism that supports their ability to function as daytime photoreceptors and promotes their survival.