For example, G90D-Rho has been found to elevate spontaneous activity to such an extent as to produce rod desensitization similar to light adaptation ( 13– 15). Various forms of night blindness and retinal degeneration have been linked to single-amino acid substitutions in rhodopsin ( 12). As the most abundant protein in rods, rhodopsin also supports the structure of the outer segment, sustaining photoreceptor health and survival ( 8– 11). Our dark-adapted visual system has an exceedingly low threshold for perceiving light ( 1), imparted largely by rhodopsin in several ways, namely, the high density of rhodopsin packed into each rod to ensure a high photon-capture ability ( 2), rhodopsin’s substantial signal amplification to provide a sizeable single-photon response ( 3– 5), and rhodopsin’s low spontaneous excitation to minimize false signaling, or dark noise ( 6, 7). Finally, D190N-Rho also provided some insight into the mechanism of spontaneous pigment excitation. Instead, the low pigment content, shortened outer-segment length, and a moderate unfolded protein response implicate protein misfolding as the major pathogenic problem. Separately, we found that much of the degeneration and shortened outer-segment length of Rho D190N/WT mouse rods was not averted by ablating rod transducin in phototransduction-also consistent with D190N-Rho’s higher isomerization activity not being the primary cause of disease. Importantly, however, this higher molecular dark activity does not translate into an overall higher cellular dark noise, owing to diminished D190N-Rho content in the rod outer segment. We replaced wild-type rhodopsin (WT-Rho) in Rho D190N/WT mouse rods with a largely “functionally silenced” rhodopsin mutant to isolate electrical responses triggered by D190N-Rho activity, and found that D190N-Rho at the single-molecule level indeed isomerizes more frequently than WT-Rho by over an order of magnitude. Both higher-than-normal spontaneous-isomerization activity and misfolding/mistargeting of the mutant protein have been proposed as causes of the disease, but neither explanation has been thoroughly examined. D190N-rhodopsin (D190N-Rho) is a well-known inherited human mutation causing retinitis pigmentosa. Numerous rhodopsin mutations have been implicated in night blindness and retinal degeneration, often with unclear etiology.
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