In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, the trafficking of rod opsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for visual function. Two key mechanisms of this process are emphasized in this manuscript: Ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene opsin to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

Unconventional myosins are molecular motors that move along actin filaments in an ATPase-dependent manner, thereby influencing intracellular cargo transport. Dysfunction of myosins due to loss-of-function mutations causes human disease phenotypes such as deafness, retinitis pigmentosa, renal failure, and hypertrophic cardiomyopathy. However, some genetic models lacking unconventional myosins do not recapitulate the retinal phenotypes observed in humans, necessitating alternative approaches. We previously showed that the myosin motor protein MYO1C is required for the trafficking of rhodopsin in mouse photoreceptors and for visual function. To investigate whether MYO1C could be nongenetically inhibited, we used the natural compound pentachloropseudilin (PCIP) to allosterically inhibit MYO1C-ATPase motor activity. PCIP treatment of COS1 cells coexpressing GFP-rhodopsin and mCherry-MYO1C resulted in an aggregation of GFP-rhodopsin protein in the cytoplasm and impaired the kinetics of rhodopsin foci movement. Conversely, GFP-rhodopsin trafficked efficiently to the plasma membrane in non-PCIP-treated COS1 cells. PCIP effects in vivo were then analyzed in wild-type mouse retinas based on evaluations of opsin trafficking, visual response measurements using ERGs, and quantification of rhodopsin recovery rates after photobleaching. Intravitreous injections of PCIP into WT mice caused significant rhodopsin mislocalization and shorter rod photoreceptor outer segments, resulting in reduced scotopic visual responses, thereby recapitulating retinitis pigmentosa phenotypes commonly observed in humans. Our study provides evidence from live-cell analysis and vertebrate retinas that using PCIP can recapitulate the retinal phenotypes observed in humans with myosin mutations. Furthermore, it confirms in a nongenetic model the requirement for MYO1C in photoreceptor opsin trafficking, maintenance of photoreceptor outer segments, and visual function.