CELLULAR PHYSIOLOGY

Cellular Physiology



Cellular Physiology

Introduction

Because the function of Trpm7 may vary in distinct cell types, and at different stages of cellular differentiation, experiments conducted on primary and immortalized cell culture models may be inadequate to fully explore the physiological roles for TRPM7 in vivo. Mouse TRPM7 mutants die during gastrulation, limiting their utility for the investigation of TRPM7 in vivo (Jin et al., 2008). Analyses of zebrafish trpm7 mutants have a greater potential to do so. Current work has in zebrafish has identified a role for Trpm7 in early melanophore survival, touch responsiveness, bone formation, and proper kidney ion regulation (Cornell, 2004; Elizondo et al., 2005; Granato et al., 1996).

Results add to our understanding of Trpm7 function in vivo. Specifically they suggest: 1) Trpm7 is necessary to prevent non-apoptotic melanophore death mediated by Trpm2 activity, 2) Trpm7 is required for proper regulation of Mg2+ in jaw formation, 3) touch unresponsiveness in trpm7 mutants is modulated by [Mg2+], and may be due to reduced dopamine signaling, 4) Trpm7 is required for differentiation of subsets of dopaminergic neurons, and promotes their survival upon exposure to a drug that elevates oxidative stress and depletes cytosolic ATP. The study of the zebrafish mitfa mutants also lead us to conclude that larval motility depends in part on the presence of pigmented melanophores, and that melanophores are required for 5-HT, L-DOPA, and DA, but not NE or Epi production.

The function of Trpm7 in melanophores

Our results demonstrate that Trpm7 is necessary in melanophores to protect against byproducts of melanin synthesis. Melanin synthesis occurs within specialized vesicles called melanosomes to protect the cell from free radicals produced as byproducts. Our current model suggests that in the absence of Trpm7 the cytosolic concentration of free radicals increases, causing Trpm2-dependent cell death. An important unresolved question is how Trpm7 prevents the formation of, or protects the cell from, produced excessive reactive oxygen species in the cytosol.

Melanosome membrane

Trpm7 may be important as an ion channel on the melanosome membrane. Melanin synthesis requires the appropriate ion balance within the melanosome. Deregulation of ion balance, for instance as by expressing a hypomorphic or null variant of the potassium-dependent sodium/calcium exchanger (Slc24a5) present in the zebrafish golden mutant, causes reduced melanin formation (Lamason et al., 2005). While these data do not indicate why loss of an ion channel on the melanosome membrane would cause death, it may indicate why surviving melanophores in trpm7 mutants have reduced pigmentation, i.e., reduced melanosome function.

Trpm7 is important for melanosome biogenesis

Trpm7 may be important in melanosome biogenesis. TRPM7 has been associated with the vesicular protein, Snapin, on cholinergic vesicles in PC-12 cells (Krapivinsky et al., 2006). Snapin expression is not confined to neurons; it is also part of complex of proteins called the Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1), which is important for the formation of lysosomes and related organelles, including melanosomes (Starcevic and Dell'Angelica, 2004). Defects in BLOC-1 components cause reduced melanosome pigmentation (Starcevic and Dell'Angelica, 2004), a feature we see in melanophores derived from trpm7 ...