The overall long-term objective of the research program in this laboratory is to elucidate the mechanisms of photoreceptor excitation by molecular genetic analyses of ERG (electroretinogram)-defective Drosophila mutants. There are two broad specific aims for the coming project period. In one, we will attempt to definitively identify the molecule that acts as the excitatory messenger to light-activated channels in Drosophila photoreceptors, TRP (transient receptor potential) &TRPL (TRP-like). The founding member of the TRP channel superfamily was discovered in Drosophila, and our lab played a prominent role in the early TRP work and coined the term, TRP. TRP channels are now known to play a key role in many human diseases. Understanding the mechanism of TRP activation is important in providing insights into the underlying causes of many of these diseases. In the second specific aim, we propose to investigate the mechanisms of visual defects found in three Drosophila mutants from three different genes, all of which were generated by chemical mutagenesis. A combination of genetic, molecular, cell biological, and electrophysiological approaches will be used for the analyses of these mutants. Two of these mutants have defects in quenching rhodopsin molecules after they are photo-excited. For one of the mutants, the gene that carries the mutation responsible for the mutant phenotype has been identified to be a Drosophila ortholog of a human Usher syndrome gene. Usher syndrome is the most common autosomal disorder of hearing and vision, characterized by congenital hearing loss, vestibular dysfunction, and retinitis pigmentosa. How mutations in Usher syndrome genes cause retinitis pigmentosa is not known. The study of this mutant may lead to the understanding of how a mutation in at least one Usher syndrome gene causes retinitis pigmentosa. The third mutant is impaired in Ca2+-dependent light adaptation. Investigation of this mutant could lead to the identification of a protein involved in the light adaptation process. Loss of light adaptation is a serious visual impairment. Identification of a molecule that plays a critical role in adaptation would be an important contribution to understanding of the adaptation process, and it could lead to the development of therapeutic intervention for this form of visual impairment
The study of Drosophila phototransduction contributed significantly to the understanding of retinal degeneration and non-image forming functions of photoreceptors in mammals, including humans. In addition, it made seminal contributions to the discovery and development of mammalian TRP channels, which is involved in almost every aspect of human health, including pain response, blood pressure regulation and immune response, among others. The proposed study will contribute further to the understanding of these and other human diseases
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