The functional cycle of visual arrestins in photoreceptor cells

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Abstract

Visual arrestin-1 plays a key role in the rapid and reproducible shutoff of rhodopsin signaling. Its highly selective binding to light-activated phosphorylated rhodopsin is an integral part of the functional perfection of rod photoreceptors. Structure-function studies revealed key elements of the sophisticated molecular mechanism ensuring arrestin-1 selectivity and paved the way to the targeted manipulation of the arrestin-1 molecule to design mutants that can compensate for congenital defects in rhodopsin phosphorylation. Arrestin-1 self-association and light-dependent translocation in photoreceptor cells work together to keep a constant supply of active rhodopsin-binding arrestin-1 monomer in the outer segment. Recent discoveries of arrestin-1 interaction with other signaling proteins suggest that it is a much more versatile signaling regulator than previously thought, affecting the function of the synaptic terminals and rod survival. Elucidation of the fine molecular mechanisms of arrestin-1 interactions with rhodopsin and other binding partners is necessary for the comprehensive understanding of rod function and for devising novel molecular tools and therapeutic approaches to the treatment of visual disorders.

Introduction

The paradigm of the receptor-initiated signaling cascade consisting of receptor (rhodopsin, Rh), G protein (transducin, Td), and effector (cGMP phosphodiesterase, PDE), was developed through studies of light-induced signaling in rod photoreceptors (Fung et al., 1981). This was long before it was appreciated that animals have a large family of G protein-coupled receptors (GPCRs or 7TMRs), of which the founding member is rhodopsin. Receptor phosphorylation as a means of its regulation was also discovered in the visual system (Liebman and Pugh, 1980) before it became clear that kinases specifically phosphorylating active receptors (G protein-coupled receptor kinases, or GRKs) “prepare” the receptor for high-affinity arrestin binding (Gurevich and Gurevich, 2004). The first member of the arrestin family, arrestin-13, was discovered twice: first as S-antigen causing uveitis (Wacker et al., 1977), then as a 48 kDa protein that binds light-activated rhodopsin (Kuhn et al., 1984). Shortly thereafter, Pfister et al (Pfister et al., 1985, Pfister et al., 1984) established that both are one and the same protein. The name “arrestin” was proposed after seminal studies by Dr. Kuhn and co-workers demonstrated that the binding of this protein to light-activated phosphorylated rhodopsin (P-Rh∗) inhibits PDE activation (Wilden et al., 1986). The first non-visual GRK (Benovic et al., 1989) and arrestin (Lohse et al., 1990), first termed β-adrenergic receptor kinase and β-arrestin, respectively, for their ability to turn off signaling by the β2-adrenergic receptor, were cloned soon thereafter. The demonstration that both can actually quench rhodopsin signaling (Lohse et al., 1992) suggested that the two-step signal shutoff, phosphorylation of active receptor followed by arrestin binding, is a fairly universal mechanism of GPCR regulation (Benovic et al., 1987). Years of homology cloning and subsequent genome projects revealed that this type of regulation is specific for animals, and that the first GRKs and “true” phosphoreceptor-binding arrestins appeared very early in pre-Metazoan evolution (Gurevich and Gurevich, 2006a; Gurevich et al., in press).

Most mammals have seven GRK subtypes, of which GRK1 (rhodopsin kinase) and GRK7 are specific for photoreceptors, with the former expressed in both rods and cones, and the latter found exclusively in cones (Lorenz et al., 1991, Shichi and Somers, 1978, Weiss et al., 1998, Weller et al., 1975). GRK1 was shown to be crucial for timely signal shutoff in both types of photoreceptors (Chen et al., 1999, Cideciyan et al., 1998). However, the fact that mice and some other nocturnal rodents with rod-dominated vision lack GRK7 in photoreceptors prevents the use of genetically modified mice to definitively determine its role in visual signaling. Mammals have four arrestin subtypes. Arrestin-1 is expressed at very high levels in both rods (Hanson et al., 2007b, Song et al., 2011, Strissel et al., 2006) and cones (Nikonov et al., 2008), whereas the cone-specific arrestin-4 (Craft et al., 1994, Murakami et al., 1993) constitutes only ∼2% of the total arrestin complement in cone photoreceptors (Nikonov et al., 2008). Nonetheless, both arrestins significantly contribute to rapid recovery of cones (Nikonov et al., 2008).

Section snippets

The mechanics of the arrestin-rhodopsin interaction

Arrestin-1 (called 48 kDa protein at the time) was identified as one of the proteins that, similar to transducin, selectively binds light-activated rhodopsin (Kuhn, 1978). However, it soon became clear that, unlike transducin, arrestin preferentially binds phosphorylated rhodopsin (Kuhn et al., 1984). In the rod, rhodopsin exists in multiple functional forms: inactive unphosphorylated (Rh), active unphosphorylated (Rh∗), inactive phosphorylated (P-Rh), and active phosphorylated (P-Rh∗). In

The biological role of arrestin-1 self-association

In rod and cone photoreceptors, arrestin-1 is the second most abundant signaling protein after the corresponding opsins (Hanson et al., 2007b, Nikonov et al., 2008, Song et al., 2011, Strissel et al., 2006). In the dark, when the bulk of arrestin-1 resides in the inner segments (IS), cell body, and synaptic terminals (see Section 4), its concentration in these compartments is expected to be >2 mM (Gurevich et al., 2007, Kim et al., 2011a, Song et al., 2011). The concentration of virtually all

Light-dependent arrestin-1 translocation in rods

Photoreceptors are neurons with a unique design: they have a specialized signaling compartment, the outer segment (OS), connected to the rest of the cell via a narrow cilium. This provides an opportunity to modulate the gain of signaling by changing the effective concentrations of the proteins involved simply by moving them in and out of the OS, rather than by changing their expression like most other cells do. Rods must have enormous concentrations of transducin (∼0.3 mM (Pugh and Lamb, 2000

The functional role of arrestin-1 concentration in the dark-adapted outer segment

Most physiological studies of rod signaling, both electroretinography (ERG) and single cell recording, use dark-adapted photoreceptors. In mammalian rods, rhodopsin shutoff appears to be faster than transducin inactivation, therefore the latter rate-limits the recovery (Krispel et al., 2006). The upper limit of active rhodopsin lifetime was determined in animals where transducin shutoff was accelerated by the over-expression of RGS9, and was estimated to be <60 ms (Krispel et al., 2006) or even

Arrestin-1 interactions with other signaling proteins

Both non-visual arrestins were reported to interact with hundreds of non-receptor signaling proteins (Xiao et al., 2007), ranging from components of the internalization machinery, such as clathrin (Goodman et al., 1996), AP2 (Laporte et al., 1999), and N-ethylmaleimide-sensitive factor (NSF) (McDonald et al., 1999) to MAP kinases activating JNK3 (McDonald et al., 2000), ERK1/2 (Luttrell et al., 2001), and p38 (Bruchas et al., 2006) and several E3 ubiquitin ligases (Ahmed et al., 2011, Bhandari

Enhanced arrestin-1 and a compensational approach to gene therapy

Mutations in >100 different genes have been shown to cause a variety of visual disorders, including several forms of retinal degeneration, that affect ∼1 in 3,000 people (Smith et al., 2009). Mechanistically, there are two distinct kinds of genetic disorders, associated with either loss or gain of function of the affected protein. Although it is still technically challenging, conceptually the path to dealing with loss-of-function mutations is fairly straightforward: cDNA encoding functional

Future directions

Although structurally and functionally arrestin-1 is one of the most studied vertebrate proteins, many important aspects of its biology still remain to be elucidated. The range of its non-rhodopsin interaction partners is only beginning to emerge, and in most cases the physiological role of these interactions remains unclear. The biological function of the robust self-association conserved among mammalian species needs to be conclusively established. Both the exact mechanism of its

Acknowledgments

The authors are grateful to our collaborators who made the studies described here possible. In particular, the authors would like to thank the labs of Drs. Paul B. Sigler, Wayne L. Hubbell, Jeannie Chen, Marie E. Burns, Emmanuele DiBenedetto, Heidi Hamm, and Candice Klug. Funded by NIH grants EY011500, GM077561, and GM081756 (VVG), NS045117 and NS065868 (EVG), and P30 core grant in vision research EY008126 (to Vanderbilt University).

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    1

    Present address: Carroll University, Waukesha, WI, USA.

    2

    Present address: Tufts University, Boston, MA, USA.

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