Targeted mutagenesis of TRPM, a Drosophila melastatin

Erwin Schrödinger Fellowschip J 1949 Targeted mutagenesis of TRPM in Drosophila Fabian MOEBIUS 26.6.2000 Intracellular Ca2+ ions regulate many important cellular processes. One mechanism to raise cytosolic Ca2+ is to increase the Ca2+ conductance of the plasma membrane. In excitable cells, voltage dependent and ligand activated channels in mediate the Ca2+ flux. The molecular identity of plasmalemmal Ca2+ conductances studied so far are activated in a G-protein and phospholipase C dependent manner. If the structure and function of these novel Ca2+ channels were known they could be excellent drug targets because of the pivotal importance of Ca2+ influx for cell differentiation, proliferation and division. Attempts to identify these channels have focused on finding mammalian homologs of TRP, anion channel which functions in Drosophila photoreceptors. TRP is activated by a G-protein coupled receptor (rhodopsin) as are many of the mammalian Ca2+ influx pathways. We reasoned that novel insights into the functions of TRP related proteins and into signal transduction pathways involving TRP channels could be achieved by finding additional members of the TRP family in Drosophila and by finding additional members of the TRP family in Drosophila and by studying the phenotypes resulting from a mutation of the corresponding genes. Signalling molecules which function upstream and downstream in the same pathway could be subsequently identified by screening either for genes with a similar phenotype or for interacting genes in screens for suppressors or enhancers. We identified one such TRP related protein (TRPM) in the almost complete genomic sequence of Drosophila. It is the only fly representative of a novel, essentially uncharacterized gene family with three other members in C. elegans and seven members in man. Two objective of the project is to inactivate the trpm gene of Drosophila to gain insight into its function in flies.