Modulation of transient receptor potential melastatin related 7 channel by presenilins

Presenilins (PS1 and PS2) are multifunctional 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 beta-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 ?E9 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 downregulation of PIP2. Conversely, PS1 and PS2 deficiency, previously shown to upregulate 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. (C) 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 865877, 2012