title: Functional INAD complexes are required to mediate degeneration in photoreceptors of the Drosophila rdgA mutant.
abstract: The TRP family of ion channels mediates a wide range of calcium-influx phenomena in eukaryotic cells. Many members of this family are activated downstream of phosphoinositide hydrolysis but the subsequent steps that lead to TRP channel activation in vivo remain unclear. Recently, the lipid products of phosphoinositide hydrolysis (such as diacylglycerol and its metabolites) have been implicated in activating TRP channels in both Drosophila and mammals. In Drosophila photoreceptors, lack of diacylglycerol kinase (DGK) activity (encoded by rdgA) leads to both constitutive TRP-channel activity and retinal degeneration. In this study, using a novel forward-genetic screen, we identified InaD, a multivalent PDZ domain protein as a suppresser of retinal degeneration in rdgA mutants. We show that InaD suppresses rdgA and that the rescue is correlated with reduced levels of phospholipase Cbeta (PLCbeta), a key enzyme for TRP channel activation. Furthermore, we show that light, Gq and PLCbeta all modulate retinal degeneration in rdgA. The results demonstrate a previously unknown requirement for a balance of PLCbeta and DGK activity for retinal degeneration in rdgA. They also suggest a key role for the lipid products of phosphoinositide hydrolysis in the activation of TRP channels in vivo.
authors.affiliation: The Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, UK.
authors.forename: Plamen
authors.initials: P
authors.lastname: Georgiev
authors.forename: Isaac
authors.initials: I
authors.lastname: Garcia-Murillas
authors.forename: Danny
authors.initials: D
authors.lastname: Ulahannan
authors.forename: Roger C
authors.initials: RC
authors.lastname: Hardie
authors.forename: Padinjat
authors.initials: P
authors.lastname: Raghu
mesh_terms: D000483:Alleles; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D054799:Phospholipase C beta; D010786:Photoreceptor Cells / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism*; D050052:TRPC Cation Channels; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D029721:Drosophila Proteins; D005136:Eye Proteins; D007527:Isoenzymes; D050052:TRPC Cation Channels; C091568:inaD protein, Drosophila; D019852:Diacylglycerol Kinase; D010738:Type C Phospholipases; D054799:Phospholipase C beta