Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes

Abstract

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous degenerative eye disease. Mutations at Arg135 of rhodopsin are associated with a severe form of autosomal dominant RP. This report presents evidence that Arg135 mutant rhodopsins (e.g., R135L, R135G, and R135W) are hyperphosphorylated and bind with high affinity to visual arrestin. Mutant rhodopsin recruits the cytosolic arrestin to the plasma membrane, and the rhodopsin-arrestin complex is internalized into the endocytic pathway. Furthermore, the rhodopsin-arrestin complexes alter the morphology of endosomal compartments and severely damage receptor-mediated endocytic functions. The biochemical and cellular defects of Arg135 mutant rhodopsins are distinct from those previously described for class I and class II RP mutations, and, hence, we propose that they be named class III. Impaired endocytic activity may underlie the pathogenesis of RP caused by class III rhodopsin mutations.

Phototransduction and retinal degeneration in Drosophila

“…The trigger that leads to the cell death resulting from endocytosis of Rh1/Arr2 complexes is still unknown. This issue may have bearing on human retinal dystrophies as the phenomenon of retinal degeneration resulting from stable rhodopsin/arrestin complexes has been documented in rodent animal models [236,237]. Mutations in Drosophila crumbs and its human homolog lead to light-induced retinal degeneration, but the mechanisms underlying these retinal degenerations are poorly understood [238,239].…”

β-Arrestin2-Mediated Internalization of Mammalian Odorant Receptors

“…Because coated vesicle-mediated transport of ORs to the base of the cilium is likely compromised because of the limited space between axonemal microtubules and the ciliary membrane, internalization of the receptor-arrestin complex via clathrin-coated vesicles could only occur in the dendritic knob, in which coated pits invaginate and numerous endocytic vesicles exist (Bannister and Dodson, 1992). Interestingly, although endocytosis has not been described as a main pathway to shut off phototransduction in photoreceptor outer segments, endocytic compartments and activity have been described in the inner segments (Cotter, 1989), and light induces internalization of rhodopsin and phosphorylated arrestin into rod cells bodies (Reme et al, 1999;Chuang et al, 2004).…”

Stable Rhodopsin/Arrestin Complex Leads to Retinal Degeneration in a Transgenic Mouse Model of Autosomal Dominant Retinitis Pigmentosa

“…For example, rhodopsin R135L mutants appear to be phosphorylated by rhodopsin kinase and bound to arrestin in vitro (Shi et al, 1998). When the R135L mutant is introduced into murine retina by in vivo electroporation, it appears to cause arrestin to accumulate around the cell body, suggesting that R135L/arrestin complex may form within these cellular compartments (Chuang et al, 2004). In addition, other naturally occurring mutations that affect the trafficking domain on the C terminus of rhodopsin will likely result in accumulation of rhodopsin in the inner segment and ONL (Sung et al, 1994;Li et al, 1996).…”

“…For example, disruption of opsin transport by conditional knock-out of kinesin-II subunit KIF3A in mouse photoreceptor cells leads to accumulation of both opsin and arrestin in the inner segment compartment of rod cells before cell death (Marszalek et al, 2000). In addition, certain mutations that affect the R135 residue of opsin lead to formation of opsin/arrestin complex and disrupted receptor-mediated endocytic functions in a cell culture system (Chuang et al, 2004). Another opsin mutant, K296E, was thought to cause ADRP by constitutive stimulation of phototransduction, a notion supported by an in vitro finding that recombinantly expressed K296E catalyzed GTP loading in transducin in a light-independent manner (Robinson et al, 1992).…”