Molecular, Cellular and Functional Changes in the Retinas of Young Adult Mice Lacking the Voltage-Gated K+ Channel Subunits Kv8.2 and K2.1

Abstract

Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) gene encoding the Kv8.2 subunit, a modulatory subunit of voltage-gated potassium (Kv) channels. In a recent study, we validated a novel mouse model of Kv8.2 deficiency at a late stage of the disease and showed that it replicates the human electroretinogram (ERG) phenotype. In this current study, we focused our investigation on young adult retinas to look for early markers of disease and evaluate their effect on retinal morphology, electrophysiology and immune response in both the Kv8.2 knockout (KO) mouse and in the Kv2.1 KO mouse, the obligate partner of Kv8.2 in functional retinal Kv channels. By evaluating the severity of retinal dystrophy in these KO models, we demonstrated that retinas of Kv KO mice have significantly higher apoptotic cells, a thinner outer nuclear cell layer and increased activated microglia cells in the subretinal space. Our results indicate that in the murine retina, the loss of Kv8.2 subunits contributes to early cellular and physiological changes leading to retinal dysfunction. These results could have potential implications in the early management of CDSRR despite its relatively nonprogressive nature in humans.

Retinoschisin and novel Na/K-ATPase interaction partners Kv2.1 and Kv8.2 define a growing protein complex at the inner segments of mammalian photoreceptors

“…To further refine the potential list of candidates, an extensive literature search was done focusing on proteins of the retina localizing to the inner segment (IS) of the photoreceptors, close to the retinal Na/K-ATPase). This focused our interest on Kv channel subunits Kv2.1 and Kv8.2, as both proteins have been localized to the photoreceptor IS membrane [ 26 – 29 ] and are known to play a predominant role in regulating phototransduction, intracellular signaling and retinal integrity [ 28 , 30 – 33 ], all processes associated with XLRS pathology.…”

“…This may be explained by the fact that ATP1A3 shows a much more widespread distribution along the different retinal cell types/retinal layers than Kv2.1 and Kv8.2. Specifically, immunohistochemical and transcriptome analyses revealed retinal Kv2.1 and Kv8.2 protein expression predominantly in photoreceptors ( www.proteinatlas.org/humanproteome/tissue/retina [ 50 ]) with a strong enrichment in photoreceptor IS [ 26 , 28 , 50 , 51 ], and, additionally, only in a subset of bipolar cells [ 50 , 52 ]. In contrast, beside a strong signal of ATP1A3 in photoreceptor IS, this protein is prominently found in the outer and inner plexiform layer, and in all retinal neurons [ 6 , 53 – 55 ].…”

“…Similar to retinoschisin-deficient mice [ 56 – 58 ], recent studies of Jiang and colleagues as well as of Inamdar and colleagues reported that Kv8.2 knockout mice reveal a significantly higher apoptotic cell count, a thinner retina, and increased microglia occurrence in the subretinal space [ 27 , 28 ]. Interestingly, the localization of Kv2.1 was found to be unaffected in Kv8.2 knockout mice [ 28 ]. Thus, the observed mislocalization of Kv2.1 in our retinoschisin-deficient mice is likely not a general consequence of retinal degeneration.…”

A Versatile Functional Interaction between Electrically Silent KVSubunits and KV7 Potassium Channels

“…Specifically, functional studies present significant challenges that can only be addressed by establishing knockout mouse models and/or a comprehensive pharmacological characterization of K V 7/K V S complexes. In this regard, it is encouraging that a first K V 8.2 mouse model is available and has been partially characterized (Hart et al ., 2019; Jiang et al , 2021). These approaches will clarify the specific roles and functional properties of K V 7-K V S interactions in biological systems.…”

Clarifying the composition of the ATP consumption factors required for maintaining ion homeostasis in mouse rod photoreceptors

“…IKx or noninactivating K + channels have recently been classified as voltage-gated K + channels (IKv) or delayed rectifier potassium currents [21]. They are comprised of heteromeric tetramers of four pore-forming α subunits, including three Kcnb1 subunits and one Kcnv2 subunit [22]. Similar to ICNG, ICa is mainly responsible for continuous Ca 2+ influx into the synaptic terminal.…”