Facultad de Ciencias de la Salud

The expressions of ion channels by Müller glial cells (MGCs) may change in response to various retinal pathophysiological conditions. There remains a gap in our understanding of MGCs' responses to photoreceptor degeneration towards finding therapies. The study explores how an inhibition of store-operated Ca2+ entry (SOCE) and its major component, Orai1 channel, in MGCs protects photoreceptors from degeneration. The study revealed increased Orai1 expression in the MGCs of retinal degeneration 10 (rd10) mice. Enhanced expression of oxidative stress markers was confirmed as a crucial pathological mechanism in rd10 retina. Inducing oxidative stress in rat MGCs resulted in increasing SOCE and Ca2+ release-activated Ca2+ (CRAC) currents. SOCE inhibition by 2-Aminoethoxydiphenyl borate (2-APB) protected photoreceptors in degenerated retinas. Finally, molecular simulations proved the structural and dynamical features of 2-APB to the target structure Orai1. Our results provide new insights into the physiology of MGCs regarding retinal degeneration and shed a light on SOCE and Orai1 as new therapeutic targets.

The retina is highly susceptible to the generation of toxic reactive oxygen species (ROS) that disrupt the normal operations of retinal cells. The glutathione (GSH) antioxidant system plays an important role in mitigating ROS. To perform its protective functions, GSH depends on nicotinamide adenine dinucleotide phosphate (NADPH) produced through the pentose phosphate pathway. This work develops the first mathematical model for the GSH antioxidant system in the outer retina, capturing the most essential components for formation of ROS, GSH production, its oxidation in detoxifying ROS, and subsequent reduction by NADPH. We calibrate and validate the model using experimental measurements, at different postnatal days up to PN28, from control mice and from the rd1 mouse model for the disease retinitis pigmentosa (RP). Global sensitivity analysis is then applied to examine the model behavior and identify the pathways with the greatest impact in control compared to RP conditions. The findings underscore the importance of GSH and NADPH production in dealing with oxidative stress during retinal development, especially after peak rod degeneration occurs in RP, leading to increased oxygen tension. This suggests that stimulation of GSH and NADPH synthesis could be a potential intervention strategy in degenerative mouse retinas with RP.

Connexins (Cx) are a family of transmembrane proteins that form gap junction intercellular channels that connect neighboring cells. These channels allow the passage of ions and other biomolecules smaller than 1 kDa, thereby synchronizing the cells both electrically and metabolically. Cxs are expressed in all retinal cell types and the diversity of Cx isoforms involved in the assembly of the channels provides a functional syncytium required for visual transduction. In this chapter, we summarize the status of current knowledge regarding Cx biology in retinal tissues and discuss how Cx dysfunction is associated with retinal disease pathophysiology. Although the contribution of Cx deficiency to retinal degeneration is not well understood, recent findings present Cx as a potential therapeutic target. Therefore, we will briefly discuss pharmacological approaches and gene therapies that are being explored to modulate Cx function and fight sight-threatening eye diseases.