Modulation of transient receptor potential melastatin related 7 channel by presenilins

Abstract

Presenilins (PS1 and PS2) are multi-functional proteins involved in a diverse array of molecular and cellular functions, including proteolysis, development, neurogenesis, synaptic plasticity, ion channel regulation and phospholipid metabolism. Mutations in presenilin genes are responsible for the majority of Familial Alzheimer disease (FAD). Consequently, FAD-associated mutations in genes encoding PS1 or PS2 lead to several key cellular phenotypes, including alterations in proteolysis of β-amyloid precursor protein (APP) and Ca2+ entry. The mechanism underlying presenilin (PS)-mediated modulation of Ca2+ entry remains to be determined. Our previous studies showed that the PS-dependent down-regulation of phosphatidylinositol-4,5-bisphosphate (PIP2) is attributable to the observed Ca2+ deficits. In this study, we attempted to identify the ion channel that is subject to the PIP2 and PS-dependent modulation. We found that Ca2+ or Zn2+ entry via the transient receptor potential melastatin 7 (TRPM7) channel was attenuated by the presence of FAD-associated PS1 mutants, such as ΔE9 and L286V. TRPM7 has been implicated in Mg2+ homeostasis and embryonic development. The intracellular delivery of PIP2 restored TRPM7-mediated Ca2+ influx, indicating that the observed deficits in Ca2+ entry are due to down-regulation of PIP2. Conversely, PS1 and PS2 deficiency, previously shown to up-regulate PIP2 levels, potentiated TRPM7-mediated Ca2+ influx. PS-dependent changes in Ca2+ influx could be neutralized by a TRPM7 channel blocker. Collectively, these results indicate that TRPM7 may underlie the Ca2+ entry deficits observed in FAD-associated PS mutants and suggest that the normal function of PS involves regulation of TRPM7 through a PIP2-dependent mechanism.

Regulation of basal autophagy by transient receptor potential melastatin 7 (TRPM7) channel

“…These results are consistent with our finding that the increased cytosolic Ca 2þ level through the ubiquitously expressed TRPM7 channel leads to the activation of basal autophagy. Since TRPM7 channel underlies the constitutive inward Ca 2þ influx in some cell types [18,19], increasing or decreasing TRPM7 channel activity may affect cytosolic Ca 2þ level, thereby, modulating the basal autophagy.…”

“…Since TRPM7 channel underlies the spontaneously constitutive Ca 2þ influx in some cells [18,19], we also tested the effect of waix on Ca 2þ influx. For this purpose, the intracellular Ca 2þ concentration ([Ca 2þ ] i ) was monitored using Fura-2 [19]. Cells were exposed to a Ca 2þ -free extracellular solution, and Ca 2þ was readded into the extracellular solution.…”

“…The TRPM7-specific shRNA (shRNA TRPM7 ) and control shRNA (shRNA SCR ) were prepared as described previously [19]. shRNAs were designed based on accession numbers in GenBank (NM_017672.3, NM_017662.4), and transfected into SH-SY5Y cells using RNAiFect transfection reagent (Qiagen).…”

“…TRPM7 channel activity is very low at physiological conditions due to tonic inhibition by intracellular Mg 2þ , MgATP, and MgGTP [16,17]. Since TRPM7 channel underlies the spontaneously constitutive Ca 2þ influx in some cells [18,19], we hypothesize that Ca 2þ influx through TRPM7 channel may regulate basal autophagy via CaMKKb-AMPK pathway. We found that increasing TRPM7 channel expression increased the level of basal autophagy via the CaMKKb-AMPK pathway.…”

The very many faces of presenilins and the γ-secretase complex

“…However, if Ca 2+ is released from intracellular stores the neurotransmitter release is becoming γ-secretase-dependent (Pratt et al 2011). Apart from γ-secretase activity, several other mechanisms by which PSs affect Ca 2+ homeostasis have been proposed: (1) formation of an ER Ca 2+ leak channel by PS holoprotein (Tu et al 2006); (2) activation of the sarco/ER Ca 2+ -ATPase (SERCA) pump (Green et al 2008); (3) increasing the activity of the inositol triphosphate receptor (InsP 3 R) Ca 2+ release channel in response to low [InsP 3 ] (Müller et al 2011a); (4) increasing the number of contact sites between ER and mitochondria, and thus favoring Ca 2+ transfer between ER and mitochondria (Zampese et al 2011); (5) potentiation of Ryanodine Receptor (RyR) activity by N-terminal fragment regulation (Rybalchenko et al 2008); and (6) PIP 2 -mediated regulation of Transient Receptor Potential Melastatin Related 7 (TRPM7) channel (Oh et al 2012). …”