Novel mechanism of massive photoreceptor degeneration caused by mutations in the trp gene of Drosophila

The Drosophila trp gene encodes a light-activated Ca2+ channel subunit, whi ch is a prototypical member of a novel class of channel proteins. Previousl y identified trp mutants are all recessive, loss-of-function mutants charac terized by a transient receptor potential and the total or near-total loss of functional TRP protein. Although retinal degeneration does occur in thes e mutants, it is relatively mild and slow in onset. We report herein a new mutant, Trp(P365), that does not display the transient receptor potential p henotype and is characterized by a substantial level of the TRP protein and rapid, semi-dominant degeneration of photoreceptors. We show that, in spit e of its unusual phenotypes, Trp(P365) is a trp allele because a Trp(P365) transgene induces the mutant phenotype in a wild-type background, and a wil d-type trp transgene in a Trp(P365) background suppresses the mutant phenot ype. Moreover, amino acid alterations that could cause the Trp(P365) phenot ype are found in the transmembrane segment region of the mutant channel pro tein. Whole-cell recordings clarified the mechanism underlying the retinal degeneration by showing that the TRP channels of Trp(P365) are constitutive ly active. Although several genes, when mutated, have been shown to cause r etinal degeneration in Drosophila, the underlying mechanism has not been id entified for any of them. The present studies provide evidence for a specif ic mechanism for massive degeneration of photoreceptors in Drosophila. Inso far as some human homologs of TRP are highly expressed in the brain, a simi lar mechanism could be a major contributor to degenerative disorders of the brain.