Abstract
Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a “sensing” ion channel to “non-sensing,” leading to ocular channelopathies like Leber’s congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a “non-sensing” channel to “sensing” would be life-changing.
Highlights
Ion channels are membrane-spanning transport proteins that facilitate the passive bidirectional flow of selective ions like sodium (Na+ ), potassium (K+ ), calcium (Ca2+ ), chloride (Cl− ), or unspecific cations (Figure 1)
The co-expression of both the mutant protein resulted in rescued channel function mutation (R141H and I366fsX18) identified in autosomal recessive bestrophinopathy (ARB) patients with comparable Cl- current to wild type (WT), attributing ARB pathogenesis to the loss of the C-terminal domain was characterized in HEK293 cells
Cacna2d4 (4a and 4b) proved to be an ideal model of pathophysiological mechanism due to CACNA2D4 dysfunctions in human. This model determined its role in the formation of Cav 1.4-pore subunit and cone-mediated signal transmission and confirmed its evolutionarily conserved function at the photoreceptor synaptic terminals [239]. Another reason to have multiple disease models is embryonic lethality caused by gene knockout, like in Kcnj13 mice, which die at postnatal day 1 (P1) [240]
Summary
Ion channels are membrane-spanning transport proteins that facilitate the passive bidirectional (into and out of cell and cell organelles) flow of selective ions like sodium (Na+ ), potassium (K+ ), calcium (Ca2+ ), chloride (Cl− ), or unspecific cations (Figure 1). K+ channels, two-pore orcell leak arethe imperative in ocular tissues like transparency [16], theand retinal ganglion cells to modulate resting membrane potential andthe cell and-activated cell excitability [17], the RPE physiology, for its interaction with the photoreceptor and cornea to regulate epithelial cell proliferation and apoptosis [13,14,15], the lens to maintain the volume and transparency [16], the retinal ganglion cells to modulate the resting membrane potential and cell ionic composition of the subretinal space [18,19]. The human genome has over 400 ion channel genes, and several mutations have been reported across several ion channel genes leading to various pathological conditions, known as channelopathies [31] These mutations may alter the structure, assembly, localization, trafficking, or functions of channel protein and, turn a sensing ion channel into a non-sensing one (Figure 1C). We discuss the future percepts of potential pharmacological and therapeutic strategies
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