Drosophila in vision research. The Friedenwald Lecture.

A genetic approach involving the use of ERG-defective Drosophila mutants, described in this article, was developed with the explicit goal of elucidating phototransduction and related photoreceptor events at the molecular level. Advances in the past 30 years have made this goal a reality. Although the phototransduction process in Drosophila is not yet fully understood, enormous strides are being made by many investigators now working in this field. In addition to elucidating phototransduction vents in invertebrate photoreceptors, works of these investigators are providing insights into the functional machinery of signaling systems in general. For example, mobilization of Ca2+ and replenishment of intracellular Ca2+ stores after their depletion is a current topic of intense interest (see, for example, references 93, 136 and 137). Study of trp mutants is providing insights into this process. Similarly, the mechanisms of inactivation of G-protein coupled receptors appear to be highly conserved in diverse transduction systems, and inactivation of Drosophila metarhodopsin is proving a valuable model system for this study. The identification of the NinaA protein and its role as chaperon and/or foldase for opsin would not have been possible without the genetic approach described in this article. In fact, study of the NinaA gene is providing fresh insights not only into the rhodopsin maturation process but also into the role of cyclophilins in general. Moreover, recent results suggest that related retina-specific proteins are also present in mammals. As valuable as the NinaA protein has been, it may be only the first of a number of such novel proteins or novel isozymes of known proteins required in the retina to be discovered through this approach. For two of the Drosophila proteins discussed in this article, NorpA and NinaA, related mammalian proteins expressed in photoreceptors have been identified, even though it seemed unlikely that such proteins would have any role in mammalian photoreceptors. A recent report suggests that the Trp protein has human homologs expressed most heavily in the brain (C. Montell, cited in reference 93). It may well be that almost any protein identified in the Drosophila retina has its counterpart(s) in mammals. Discovery of these mammalian homologs of Drosophila proteins will probably spur new lines of investigation in mammalian photoreceptor function. For example, because no role had been assigned to PLC in cone phototransduction, the discovery that NorpA-homologous PLCs are present in cone outer segments raises questions about what role(s) these PLCs might play in signal transduction in cone outer segments.