Heteromeric K_V2/K_V8.2 Channels Mediate Delayed Rectifier Potassium Currents in Primate Photoreceptors

Abstract

Silent voltage-gated potassium channel subunits (KS) interact selectively with members of the K2 channel family to modify their functional properties. The localization and functional roles of these silent subunits remain poorly understood. Mutations in the KS subunit, K8.2 (), 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 K8.2-containing channels in mouse, macaque, and human photoreceptors of either sex. In human retina, K8.2 colocalized with K2.1 and K2.2 in cone inner segments and with K2.1 in rod inner segments. K2.1 and K2.2 could be coimmunoprecipitated with K8.2 in retinal lysates indicating that these subunits likely interact directly. Retinal K2.1 was less phosphorylated than cortical K2.1, 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 K8.2, and low levels of K2.1 phosphorylation shift the activation range of K2 channels to align with the operating range of rod and cone photoreceptors. Our data indicate a role for K2/K8.2 channels in human photoreceptor function and suggest that the visual deficits in patients with mutations arise from inadequate resting activation of K channels in rod and cone inner segments. Mutations in a voltage-gated potassium channel subunit, K8.2, 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 K8.2 channels in primate photoreceptors. We show that the K8.2 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 gene encoding K8.2.

Membrane conductances of mouse cone photoreceptors

“…5 C, red). It resembles the sustained K + currents previously recorded from salamander (Beech and Barnes, 1989) and primate photoreceptors (Gayet-Primo et al, 2018). (B) After cones treated as in A had reached a steady-state resting current with little or no response at V m = −50, responses were recorded to the same light stimulus at holding potentials from −70 to −10 mV in steps of 20 mV.…”

“…5, A and C); and a more sustained voltage-gated potassium current, i k,sus , which is active at physiological membrane voltages and blocked by TEA (Fig. 5, B and C), similar to the i KX of salamander rods (Beech and Barnes, 1989) and the K V 8.2/K V 2 current of primate photoreceptors (Gayet-Primo et al, 2018).…”

Kv2.1 channels play opposing roles in regulating membrane potential, Ca 2+ channel function, and myogenic tone in arterial smooth muscle

“…1 C and D). Immunoblots of WT arteries showed prominent bands at 110 kDa, the expected molecular mass of Kv2.1 (19,31). This band was absent in lysates obtained from Kv2.1 −/− arteries.…”

Expression and Localization ofKcne2in the Vertebrate Retina

“…Loss-of-function mutations in K v 8.2 cause a hereditary retinal disorder known as cone dystrophy with supernormal rod response (CDSRR), most likely by increasing potassium conductance (I k,x ). 38,39 Interestingly, although K v 8.2 and K v 2.1 are expressed in both rods and cones, CDSRR is characterized by a selective early-onset degeneration of cones, whereas rods are more resilient. It is conceivable that in cones the expression of Kcne2 modulates K v 2.1 in a way that the absence of functional Kv8.2 in CDSRR has an even higher impact on I k,x and thereby promotes cone susceptibility.…”