The present manuscript reveals three major and novel findings in rods bearing the
P23H mutation, the leading cause of RP. First, if
X. laevis tadpoles carrying the rhodopsin
P23H mutation are reared in darkness, mutant rods have functional and almost normal phototransduction machinery. Second, when exposed to a bright light lasting 1 second (
Fig. 4), their photoresponses are irreversibly prolonged. Third, when light exposure is maintained for 12 minutes (
Fig. 5), significant OS shedding occurs and RD is initiated. Therefore, the first step leading to RD is the prolongation of photoresponses associated with the photoisomerization of 6 × 10
4 to 5 × 10
5 Rh*, equivalent to 4 to 32 P23H rhodopsins per disc. However, initiation of dramatic morphologic changes identifiable by light microscopy, such as OS shedding, requires 1 to 2 orders of magnitude greater Rh*. How can we account for this extreme sensitivity? While previous phototransduction models were based on freely diffusing rhodopsin, recent studies indicate that rhodopsins—and presumably bP23H rhodopsin—are organized in discs along parallel tracks of dimers.
42–45 Signal amplification requires multiple diffusion encounters, likely involving rhodopsins anchored in tracks of dimers while other phototransduction components diffuse more freely.
42,46 The photoresponse prolongation observed in
bP23H rods is consistent with impaired rhodopsin shutoff. Transducin GTPase, arrestin, rhodopsin kinase, and RGS9 are involved in phototransduction shutoff and could have roles in this impairment.