TRPM Channels Mediate Zinc Homeostasis and Cellular Growth during Drosophila Larval Development

Abstract

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.

Transient Receptor Potential Melastatin 1 (TRPM1) Is an Ion-conducting Plasma Membrane Channel Inhibited by Zinc Ions

“…Both are also highly permeable to divalent cations, including Zn 2ϩ ions (36,37,(45)(46)(47). This is also true for dTRPM, the only TRPM channel present in Drosophila melanogaster (48). The most striking difference in primary sequence between TRPM1 on one hand and TRPM3, TRPM6, TRPM7, and dTRPM on the other hand is the addition of seven amino acids in the pore region (the LYAMEIN motif), making it a prime candidate for mediating the zinc sensitivity of TRPM1.…”

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

“…Here we show that most TRPM7 forms intracellular , whereas TRPM8 may release Ca 2+ from the ER in some cell types (65,66). The Drosophila TRPM channel, proposed to release Zn 2+ from intracellular stores during larval development, exhibits TRPM7-like currents (67). We now include TRPM7 in the class of functional intracellular TRP channels.…”

Systematic functional characterization of putative zinc transport genes and identification of zinc toxicosis phenotypes inDrosophila melanogaster

“…These larvae displayed distinct reductions in body size in comparison to wild-type larvae and pupae (J.C.L., unpublished). Similar delays in larval development due to disrupted zinc homeostasis by suppression of dZnT63C (Wang et al, 2009) or mutation of the ion channel gene dTRPM (Georgiev et al, 2010) have previously been reported, with melanotic accumulations attributed to prolonged larval growth phases rather than a specific disruption to zinc levels (Georgiev et al, 2010). Zinc transport in Drosophila This suppression/over-expression screen was repeated using two different Gal4 driver lines.…”

“…Furthermore, it has recently been shown that proteins other than ZIP and ZnT may be able to transport zinc. Mammalian TRPM3 has been demonstrated to mediate the influx of zinc into pancreatic -cells (Wagner et al, 2010) and loss of function of the Drosophila TRPM channel gene, dTRPM, resulted in larval growth inhibition and cell autonomous growth defects associated with defects in mitochondrial structure and function (Georgiev et al, 2010). All of the dTRPM mutant phenotypes could be phenocopied by zinc depletion and partially rescued by zinc supplementation (Georgiev et al, 2010), indicating a key role for dTRPM in regulating zinc homeostasis in a specific cellular organelle, although the cellular localization of this channel is not yet known.…”