Disease relevance of Arr2

• We further demonstrate that if the interaction between Arr2 and AP-2 is blocked, this also results in retinal degeneration in an otherwise wild-type background [1].
• We propose that the sequestering of arrestin to membranes is a possible mechanism for retinal disease associated with previously identified rhodopsin alleles in humans [2].
• Vertebrate arrestin interacts with rhodopsin in phototransduction and has been associated with an autoimmune form of uveitis in primates [3].

Psychiatry related information on Arr2

• Odorant-specific requirements for arrestin function in Drosophila olfaction [4].

High impact information on Arr2

• In this paper, we develop a theory that describes the kinetics of inactivation of the G protein-coupled receptor rhodopsin based on the rate of arrestin binding and test the theory using a combination of genetic and electrophysiological techniques in Drosophila photoreceptors [5].
• The results demonstrate that the rate of arrestin binding determines the kinetics of receptor inactivation in vivo and thus is the event that controls signal amplification at the first step of this G protein-coupled transduction cascade [5].
• Although visual arrestin has been shown to quench the catalytic activity of photoexcited, phosphorylated rhodopsin in a reconstituted system, its role in the intact rod cell remains unclear because phosphorylation alone reduces the catalytic activity of rhodopsin [6].
• The intensity dependence of the photoresponse in rods lacking arrestin further suggests that, although arrestin is required for normal signal termination, it does not participate directly in light adaptation [6].
• Analysis of the light response in these mutants shows that the Arr1 and Arr2 proteins are mediators of rhodopsin inactivation and are essential for the termination of the phototransduction cascade in vivo [7].

Biological context of Arr2

• We further find that Rh1 C-terminal phosphorylation is essential for light-induced endocytosis and also for translocation of Arr1, but not Arr2, from dark-adapted photoreceptor cytoplasm to photosensory membrane rhabdomeres [8].
• RESULTS: We report that Arr1, but not Arr2, is essential for normal, light-induced rhodopsin endocytosis [8].
• Photoreceptor cell death caused by loss of Arr1 is strongly suppressed by coordinate loss of Arr2 [8].
• We showed that defects in ninaC resulted in a long-term adaptation phenotype similar to that which occurred in arr2 mutants [9].
• The encoded protein has 401 amino acid residues and a molecular mass of 44,972 daltons, and it shares approximately 42 percent amino acid sequence identity with arrestin (S-antigen), which has been proposed to quench the light-induced cascade of guanosine 3',5'-monophosphate hydrolysis in vertebrate photoreceptors [10].

Anatomical context of Arr2

• Also distinct from Arr2, Arr1 is essential for light-independent photoreceptor survival [8].
• As the olfactory deficits vary according to chemical identity and concentration, they indicate that a spectrum of arrestin activity is essential for odor processing depending upon the particular olfactory pathway involved [4].
• Interestingly, we found that the Arr2 phosphorylation mutant was still capable of binding to rhodopsin; however, it was unable to release from membranes once rhodopsin had converted back to its inactive form [2].
• We find that phosrestin I (PRI), a Drosophila homolog of vertebrate photoreceptor arrestin, undergoes light-induced phosphorylation on a subsecond time scale which is faster than that of any other protein in vivo [11].
• We observed that Drosophila PRI exists in the random preparation, but it also exists in other subcellular fractions [12].

Associations of Arr2 with chemical compounds

• The phosphorylation of this arrestin-like protein in vivo may therefore be triggered by a Ca2+ signal that is likely to be regulated by light-activated phosphoinositide-specific phospholipase C [10].
• Nonvisual arrestin oligomerization and cellular localization are regulated by inositol hexakisphosphate binding [13].
• Clones encoding proteins homologous to arrestin have been isolated from antennal cDNA libraries of Locusta migratoria and Heliothis virescens [14].
• Suppression of degeneration in arrestin mutant flies expressing ceramidase correlated with a decrease in ceramide levels [15].

Enzymatic interactions of Arr2

• Here we present biochemical evidence that a CaM PK that phosphorylates arrestin in Limulus eyes is structurally similar to mammalian CaM PK II [16].

Regulatory relationships of Arr2

• Phosrestin I undergoes the earliest light-induced phosphorylation by a calcium/calmodulin-dependent protein kinase in Drosophila photoreceptors [11].

Other interactions of Arr2

• These data demonstrate that the light-dependent translocation of Arr2 into the rhabdomeres requires PI-mediated interactions between Arr2 and the NINAC myosin III [9].
• Here we demonstrate that both arrestin and rhodopsin undergo light-dependent endocytosis in a PLC mutant background [17].
• They show that arrestin is carried into the light-sensitive microvilli by phosphoinositide-enriched vesicles driven by a myosin motor [18].
• Calcium/calmodulin-dependent protein kinase II and arrestin phosphorylation in Limulus eyes [16].
• Phosrestide-1, a peptide derived from the Drosophila photoreceptor protein phosrestin I, is a potent substrate for Ca2+/calmodulin-dependent protein kinase II from rat brain [19].

Analytical, diagnostic and therapeutic context of Arr2

• Proteins were resolved by polyacrylamide gel electrophoresis (PAGE) and subjected to immunoblot analysis using antibodies directed to rhodopsin, NinaA, Arr1, and Arr2 [20].
• Immunocytochemistry at the EM level revealed a distribution of both Drosophila and Musca PRI epitopes in membranous vesicular structures in the cytosol as well as in the rhabdomeric microvillar membranes where the visual pigment, rhodopsin, exists [12].
• (2) Rabbit antibodies raised against Musca PRI, against bovine arrestin, and against a synthetic peptide based on the Drosophila PRI sequence stained the Drosophila and Musca PRIs specifically on 1 and 2-dimensional Western immunoblots [12].
• Native gel electrophoresis, gel filtration, and analytical ultracentrifugation demonstrated the ability of IP(6) to promote arrestin-2 oligomerization via the two crystallographically defined ligand-binding locations [13].
• 1 microm frozen sections were cut on an ultracryomicrotome, then stained with antibodies specific for rhodopsin or arrestin [21].

References