title: Modulation of transient receptor potential melastatin related 7 channel by presenilins.
abstract: 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 β-amyloid precursor protein (APP) and Ca(2+) entry. The mechanism underlying presenilin (PS)-mediated modulation of Ca(2+) 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 Ca(2+) deficits. In this study, we attempted to identify the ion channel that is subject to the PIP2 and PS-dependent modulation. We found that Ca(2+) or Zn(2+) 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 Mg(2+) homeostasis and embryonic development. The intracellular delivery of PIP2 restored TRPM7-mediated Ca(2+) influx, indicating that the observed deficits in Ca(2+) entry are due to downregulation of PIP2. Conversely, PS1 and PS2 deficiency, previously shown to upregulate PIP2 levels, potentiated TRPM7-mediated Ca(2+) influx. PS-dependent changes in Ca(2+) influx could be neutralized by a TRPM7 channel blocker. Collectively, these results indicate that TRPM7 may underlie the Ca(2+) 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.
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Hyun Geun
authors.initials: HG
authors.lastname: Oh
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Chun
authors.forename: Yonjung
authors.initials: Y
authors.lastname: Kim
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Youn
authors.forename: Sora
authors.initials: S
authors.lastname: Shin
authors.forename: Myoung Kyu
authors.initials: MK
authors.lastname: Park
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D053763:Presenilins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D053764:Presenilin-1; D053763:Presenilins; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D054801:Phosphoinositide Phospholipase C; D015032:Zinc; D002118:Calcium
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