Manganese Suppresses the Haploinsufficiency of Heterozygous Cells and Stimulates the TRPY1-Dependent Release of Vacuolar Ca under H₂O₂ Stress.

Transient potential receptor (TRP) channels are conserved cation channels found in most eukaryotes, known to sense a variety of chemical, thermal or mechanical stimuli. The TRPY1 is a TRP channel with vacuolar localization involved in the cellular response to hyperosmotic shock and oxidative stress. In this study, we found that diploid cells with heterozygous deletion in gene are haploinsufficient when grown in synthetic media deficient in essential metal ions and that this growth defect is alleviated by non-toxic Mn surplus. Using cells expressing the Ca-sensitive photoprotein aequorin we found that Mn augmented the Ca flux into the cytosol under oxidative stress, but not under hyperosmotic shock, a trait that was absent in the diploid cells with homozygous deletion of gene. TRPY1 activation under oxidative stress was diminished in cells devoid of Smf1 (the Mn-high-affinity plasma membrane transporter) but it was clearly augmented in cells lacking Pmr1 (the endoplasmic reticulum (ER)/Golgi located ATPase responsible for Mn detoxification via excretory pathway). Taken together, these observations lead to the conclusion that increased levels of intracytosolic Mn activate TRPY1 in the response to oxidative stress.