Heteromeric KV2/KV8.2 Channels Mediate Delayed Rectifier Potassium Currents in Primate Photoreceptors

Silent voltage-gated potassium channel subunits (K_VS) interact selectively with members of the K_V2 channel family to modify their functional properties. The localization and functional roles of these silent subunits remain poorly understood. Mutations in the K_VS subunit, K_V8.2 (KCNV2), lead to severe visual impairment in humans, but the basis of these deficits remains unclear. Here, we examined the localization, native interactions, and functional properties of K_V8.2-containing channels in mouse, macaque, and human photoreceptors of either sex. In human retina, K_V8.2 colocalized with K_V2.1 and K_V2.2 in cone inner segments and with K_V2.1 in rod inner segments. K_V2.1 and K_V2.2 could be coimmunoprecipitated with K_V8.2 in retinal lysates indicating that these subunits likely interact directly. Retinal K_V2.1 was less phosphorylated than cortical K_V2.1, a difference expected to alter the biophysical properties of these channels. Using voltage-clamp recordings and pharmacology, we provide functional evidence for Kv2-containing channels in primate rods and cones. We propose that the presence of K_V8.2, and low levels of K_V2.1 phosphorylation shift the activation range of K_V2 channels to align with the operating range of rod and cone photoreceptors. Our data indicate a role for K_V2/K_V8.2 channels in human photoreceptor function and suggest that the visual deficits in patients with KCNV2 mutations arise from inadequate resting activation of K_V channels in rod and cone inner segments.

SIGNIFICANCE STATEMENT Mutations in a voltage-gated potassium channel subunit, K_V8.2, underlie a blinding inherited photoreceptor dystrophy, indicating an important role for these channels in human vision. Here, we have defined the localization and subunit interactions of K_V8.2 channels in primate photoreceptors. We show that the K_V8.2 subunit interacts with different Kv2 channels in rods and cones, giving rise to potassium currents with distinct functional properties. Our results provide a molecular basis for retinal dysfunction in patients with mutations in the KCNV2 gene encoding K_V8.2.