In the visual system, the activation of rhodopsin by a photon of light initiates a chain of events referred to as the phototransduction cascade. The inactivation of the cascade at one level is achieved by the binding of the regulatory protein arrestin to rhodopsin. The normally transient interaction between rhodopsin and arrestin is stabilized in certain genetic backgrounds where arrestin remains in the unphosphorylated form. The accumulation of these stable complexes between rhodopsin and arrestin are direct mediators of photoreceptor cell apoptosis and retinal degeneration. The initial step in photoreceptor cell degeneration is the internalization of the rhodopsin/arrestin complexes into the cell body via receptor-mediated endocytosis. The rhodopsin accumulates in insoluble aggregates within the photoreceptor cytoplasm. This defines a novel apoptotic signaling pathway that is responsible for retinal degeneration in a number of Drosophila mutants. Interestingly, in several different forms of autosomal dominant retinitis pigmentosa stable complexes between rhodopsin and arrestin have been observed. Moreover, many neuronal degenerative disorders are characterized by the intracellular accumulation of protein complexes, suggesting that this may be a common apoptotic mechanism that is used in a wide variety of diseases. In an effort to further characterize this novel apoptotic pathway three experimental approaches will be undertaken. 1). We will determine if an interaction between arrestin and the AP2 heterotetramer is essential for rhodopsin endocytosis. 2). We will examine the role of endosomal trafficking of rhodopsin and arrestin in the activation of cell death. 3). A genetic screen will be conducted to isolate gene products involved in this novel apoptotic signaling pathway. Gene products involved in coupling rhodopsin/arrestin complex formation with the cell death machinery will be identified and characterized.
|Gavin, Brendan A; Arruda, Susan E; Dolph, Patrick J (2007) The role of carcinine in signaling at the Drosophila photoreceptor synapse. PLoS Genet 3:e206|