TY - JOUR T1 - The role of the voltage-gated potassium channel proteins Kv8.2 and Kv2.1 in vision and retinal disease: insights from the study of mouse gene knock-out mutations JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0032-19.2019 SP - ENEURO.0032-19.2019 AU - Nathan S Hart AU - Jessica K Mountford AU - Valentina Voigt AU - Paula Fuller-Carter AU - Melanie Barth AU - Jeanne M Nerbonne AU - David M Hunt AU - Livia S Carvalho Y1 - 2019/02/11 UR - http://www.eneuro.org/content/early/2019/02/06/ENEURO.0032-19.2019.abstract N2 - Mutations in the KCNV2 gene, which encodes the voltage-gated K+ channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the KCNB1 gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilised knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 KO mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. OCT imaging and immunohistochemistry indicate that the changes in 6 months old Kv8.2 KO retinae are largely limited to the outer nuclear layer, while outer segments appear intact. In addition, there is a significant increase in TUNEL positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric or lack channels completely, has provided further insights into the role of K+ channels in the generation of the a-, b- and c-wave components of the ERG.Significance statement Heterotetrameric Kv voltage-gated K+ channels are formed by two subunits, Kv8.2 and Kv2.1, encoded respectively by the KCNV2 gene and KCNB1 gene. Kv8.2 subunits act as modifiers of channel activity but are not capable of forming functional homomeric channels. Mutations in KCNV2 result in a blinding disorder that combines photoreceptor dystrophy with an enhanced rod ERG, a feature that is generally diagnostic for the disorder. In this study, mouse models with knock-out mutations of the Kcnv2 and Kcnb1 genes have been used to study of the function of Kv channels in the response to light stimulation as analysed by ERG recordings in order to further our understanding of the role of these channels in vision and disease. ER -