TRPM channels mediate zinc homeostasis and cellular growth during Drosophila larval development.
TRPM channels have emerged as key mediators of diverse physiological functions. However, the ionic permeability relevant to physiological function in vivo remains unclear for most members. We report that the single Drosophila TRPM gene (dTRPM) generates a conductance permeable to divalent cations, especially Zn(2+) and in vivo a loss-of-function mutation in dTRPM disrupts intracellular Zn(2+) homeostasis. TRPM deficiency leads to profound reduction in larval growth resulting from a decrease in cell size and associated defects in mitochondrial structure and function. These phenotypes are cell-autonomous and can be recapitulated in wild-type animals by Zn(2+) depletion. Both the cell size and mitochondrial defect can be rescued by extracellular Zn(2+) supplementation. Thus our results implicate TRPM channels in the regulation of cellular Zn(2+) in vivo. We propose that regulation of Zn(2+) homeostasis through dTRPM channels is required to support molecular processes that mediate class I PI3K-regulated cell growth.
Georgiev
Plamen
P
Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Okkenhaug
Hanneke
H
Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Drews
Anna
A
Emmy Noether Research Group, Experimentelle und Klinische Pharmakologie und Toxikologie, Uniklinikum des Saarlandes, 66421 Homburg, Germany.
Wright
David
D
Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3AT, UK.
Lambert
Sachar
S
Emmy Noether Research Group, Experimentelle und Klinische Pharmakologie und Toxikologie, Uniklinikum des Saarlandes, 66421 Homburg, Germany.
Flick
Melanie
M
Emmy Noether Research Group, Experimentelle und Klinische Pharmakologie und Toxikologie, Uniklinikum des Saarlandes, 66421 Homburg, Germany.
Carta
Valentina
V
Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Martel
Cecile
C
Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Oberwinkler
Johannes
J
Emmy Noether Research Group, Experimentelle und Klinische Pharmakologie und Toxikologie, Uniklinikum des Saarlandes, 66421 Homburg, Germany.
Raghu
Padinjat
P
Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: praghu@ncbs.res.in.
D000818:Animals; D048429:Cell Size; D004330:Drosophila / Q000254:growth & development; D006706:Homeostasis; D007814:Larva / Q000254:growth & development*; D008928:Mitochondria / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases; D050053:TRPM Cation Channels / Q000172:deficiency / Q000502:physiology*; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
D050053:TRPM Cation Channels; D019869:Phosphatidylinositol 3-Kinases; D015032:Zinc