Cone Arrestin

      With the identification of a superfamily of arrestin proteins (Craft, Whitmore, and Wiechmann, 1994; Craft and Whitmore, 1995), the function of the newest member, cone arrestin, is critical for our understanding of cone opsin photoreceptor signal transduction. Cone arrestin mutations may cause a human X-linked cone dystrophy that maps to the genetic loci of cone arrestin, a gene discovered by Dr. Craft. We have characterized the human, Xenopus, mouse and chicken cone arrestin, focusing our future studies on the mouse model to analyze the gene structure/function. In parallel basic science experiments, her group has the knock out constructs introduced into embryonic stem cells for the mouse cone arrestin gene to examine the electrophysiological, biochemical and morphological phenotype of the cone transduction machinery without this cone opsin regulator.

Background:

Arrestins are a super-family of modulatory proteins that down-regulate phosphorylated G-protein coupled receptors. This family includes visual arresting (rod arrestin and cone/X-arrestin), P-arrestin I and 2, and chemosensory insect arresting. The first arrestin member to be molecularly described was S-antigen, renamed rod arrestin. This arrestin has been studied extensively during recent years. It quenches light-induced phototransduction in rod photoreceptor cells by binding to activated, phosphorylated rhodopsin. Subsequently, P-arrestin was identified using the original arrestin in a CDNA low stringency screen and was shown to play a similar role in the regulation of Padrenergic receptors and many other G-protein coupled receptors. Later, P-arrestin was further shown as an adapter in clathrin-coated vesicle-mediated endocytosis in receptor resensitization. Recent work also suggests that P-arrestin I mediates c-Src recruitment as an adapter in the formation of P2-adrenergic receptor-Src tyrosine kinase complex, which initiates signal transduction in mitogen-activated protein kinase pathways. 

Cone arrestin (CARR, also X-arrestin, Arrestin 3) was initially cloned in our laboratory and another group independently, as an X-chromosomal-linked human retina-specific CDNA. The human CARR gene maps to Xcen-Xq22, and encodes 388-amino-acid protein (45 KDa) showing 58% homology with bovine P-arrestin, 52% homology with human P-arrestin and 49% homology with human rod arrestin. Dual immunofluorescent confocal studies using antisera specific for the C-terminal of CARR and red/green or blue opsin demonstrated that CARR is expressed specifically in all cone photoreceptors from the synapse to the outer segment. No CARR was observed in the rod photoreceptors. CARR orthologs have been identified from other vertebrates like killifish, bullfrog, leopard frog, clawed frog, mouse, and bovine. Because of its significant homology to rod and P-arrestin, and its cone-specific localization, we hypothesize that CARR plays a crucial regulatory role in the cone phototransduction, similar to that of rod arrestin in rod photoreceptors and P-arrestin in the neuronal cells with P-adrenergic receptors. The actual function of CARR is still unknown.