Rhodopsin is a seven-transmembrane G protein-coupled receptor (GPCR) and is the main component of the photoreceptor outer segment (OS), a ciliary compartment essential for vision. Because the OSs are incapable of protein synthesis, rhodopsin must first be synthesized in the inner segments (ISs) and subsequently trafficked across the connecting cilia to the OSs where it participates in the phototransduction cascade. Rapid turnover of the OS necessitates a high rate of synthesis and efficient trafficking of rhodopsin to the cilia. This cilia-targeting mechanism is shared among other ciliary-localized GPCRs. In this review, we will discuss the process of rhodopsin trafficking from the IS to the OS beginning with the trafficking signals present on the protein. Starting from the endoplasmic reticulum and the Golgi apparatus within the IS, we will cover the molecular components assisting the biogenesis and the proper sorting. We will also review the confirmed binding and interacting partners that help target rhodopsin toward the connecting cilium as well as the cilia-localized components which direct proteins into the proper compartments of the OS. While rhodopsin is the most critical and abundant component of the photoreceptor OS, mutations in the rhodopsin gene commonly lead to its mislocalization within the photoreceptors. In addition to covering the trafficking patterns of rhodopsin, we will also review some of the most common rhodopsin mutants which cause mistrafficking and subsequent death of photoreceptors. Toward the goal of understanding the pathogenesis, three major mechanisms of aberrant trafficking as well as putative mechanisms of photoreceptor degeneration will be discussed.
Keywords: Connecting cilium; Dynein; GPCR; Outer segment; Phototransduction; Primary cilia; Retina; Retinitis pigmentosa; Rhodopsin; Rod photoreceptor.
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