The Na+/Ca2+, K+ exchanger 2 modulates mammalian cone phototransduction

Calcium ions (Ca²⁺) modulate the phototransduction cascade of vertebrate cone photoreceptors to tune gain, inactivation, and light adaptation. In darkness, the continuous current entering the cone outer segment through cGMP-gated (CNG) channels is carried in part by Ca²⁺, which is then extruded back to the extracellular space. The mechanism of Ca²⁺ extrusion from mammalian cones is not understood. The dominant view has been that the cone-specific isoform of the Na⁺/Ca²⁺, K⁺ exchanger, NCKX2, is responsible for removing Ca²⁺ from their outer segments. However, indirect evaluation of cone function in NCKX2-deficient (Nckx2^-/-) mice by electroretinogram recordings revealed normal photopic b-wave responses. This unexpected result suggested that NCKX2 may not be involved in the Ca²⁺ homeostasis of mammalian cones. To address this controversy, we examined the expression of NCKX2 in mouse cones and performed transretinal recordings from Nckx2^-/- mice to determine the effect of NCKX2 deletion on cone function directly. We found that Nckx2^-/- cones exhibit compromised phototransduction inactivation, slower response recovery and delayed background adaptation. We conclude that NCKX2 is required for the maintenance of efficient Ca²⁺ extrusion from mouse cones. However, surprisingly, Nckx2^-/- cones adapted normally in steady background light, indicating the existence of additional Ca²⁺-extruding mechanisms in mammalian cones.