The Role of Arrestins in Visual and Disease Processes of the Eye - Progress in Molecular Biology and Translational Science - page 241

Although the function of translocation of arrestins in photoreceptors is
not yet understood, the mechanism underlying arrestin1 translocation has
been partially elucidated. Several elegant studies have shown that the tran-
sition zone of the cilium does not present a significant barrier to diffusion of
soluble proteins, including fusions of arrestin1 with GFP, and that diffusional
rates alone are sufficient to account for the rate at which arrestin1 translo-
cates during both light and dark adaptations. 57-59 The diffusion model sug-
gests that different binding partners primarily drive the diffusion-mediated
translocation of arrestin1. During light exposure, activated rhodopsin serves
as the principal light-driven impetus to draw arrestin1 by diffusion through
the transition zone, and then be retained in the outer segment by binding to
light-activated rhodopsin. Direct evidence supporting this model comes
from studies using transgenic mice expressing various levels of rhodopsin.
In these mice, the fraction of arrestin1 that translocates to the outer segments
during light adaptation is directly proportional to the level of rhodopsin
expressed. 60 One puzzling observation that does not fit with this model is
that in Xenopus that are continuously exposed to light, arrestin1 is not
retained in the outer segments as occurs in mammalian rods, but returns
to the inner segments after illuminations lasting longer than 60 min. 52
How this observation reconciles with the idea of arrestin1 binding to acti-
vated rhodopsin as the principal driving force for arrestin1 translocation to
the outer segment is not clear.
For selective partitioning of arrestin1 in the inner segment of dark-
adapted rods, two potential explanations have put forward—steric exclusion
of arrestin1 tetramers 59 and inner segment binding partners. 61 In a recent
analysis of the cytoplasmic space in the disc-filled outer segment, Calvert
and his collaborators have shown that steric exclusion can result in as much
as 90% of selective partitioning of proteins to the inner segments for cyto-
solic proteins greater than 80 kDa. 59 Although arrestin1 is only 45 kDa in
size, it forms multimers, forming dimers and tetramers at 40 m M and
10 m M, respectively, 62-64 well within the physiological millimolar con-
centration of arrestin1 measured in photoreceptors. 51,65 This tetrameric size
(180 kDa) would be excluded from most of the cytosolic volume of the
outer segment and could thus account for much of the dark-adapted distri-
bution of arrestin1 that is observed. Note that arrestin1 binds activated rho-
dopsin in its monomeric form 64 and would thus not be excluded from the
space between discs in the outer segments. Direct interaction of arrestin1
with inner segment proteins could also account for selective partitioning
of arrestin1 to the inner segment in the absence of binding to rhodopsin