Estrogen receptor α promotes Cav1.2 ubiquitination and degradation in neuronal cells and in APP/PS1 mice

Yu Jie Lai, Bing Lin Zhu, Fei Sun, Dong Luo, Yuan Lin Ma, Bio Luo, Jing Tang, Ming Jian Xiong, Lu Liu, Yan Long, Xiao Tong Hu, Ling He, Xiao Juan Deng, John H. Zhang, Jian Yang, Zhen Yan, Guo Jun Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Cav1.2 is the pore-forming subunit of L-type voltage-gated calcium channel (LTCC) that plays an important role in calcium overload and cell death in Alzheimer's disease. LTCC activity can be regulated by estrogen, a sex steroid hormone that is neuroprotective. Here, we investigated the potential mechanisms in estrogen-mediated regulation of Cav1.2 protein. We found that in cultured primary neurons, 17β-estradiol (E2) reduced Cav1.2 protein through estrogen receptor α (ERα). This effect was offset by a proteasomal inhibitor MG132, indicating that ubiquitin–proteasome system was involved. Consistently, the ubiquitin (UB) mutant at lysine 29 (K29R) or the K29-deubiquitinating enzyme TRAF-binding protein domain (TRABID) attenuated the effect of ERα on Cav1.2. We further identified that the E3 ligase Mdm2 (double minute 2 protein) and the PEST sequence in Cav1.2 protein played a role, as Mdm2 overexpression and the membrane-permeable PEST peptides prevented ERα-mediated Cav1.2 reduction, and Mdm2 overexpression led to the reduced Cav1.2 protein and the increased colocalization of Cav1.2 with ubiquitin in cortical neurons in vivo. In ovariectomized (OVX) APP/PS1 mice, administration of ERα agonist PPT reduced cerebral Cav1.2 protein, increased Cav1.2 ubiquitination, and improved cognitive performances. Taken together, ERα-induced Cav1.2 degradation involved K29-linked UB chains and the E3 ligase Mdm2, which might play a role in cognitive improvement in OVX APP/PS1 mice.

Original languageEnglish
Article numbere12961
JournalAging Cell
Volume18
Issue number4
DOIs
StatePublished - Aug 2019

ASJC Scopus Subject Areas

  • Aging
  • Cell Biology

Keywords

  • Alzheimer’s disease
  • Cav1.2
  • Estrogen receptor α
  • K29
  • Mdm2
  • ubiquitination
  • Estradiol/pharmacology
  • Mice/embryology
  • Calcium Channels, L-Type/metabolism
  • Humans
  • Phenols/pharmacology
  • Gene Knockdown Techniques
  • Transfection
  • Oligopeptides/genetics
  • Female
  • Ubiquitin/metabolism
  • Disease Models, Animal
  • Leupeptins/pharmacology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-mdm2/genetics
  • Estrogen Receptor alpha/agonists
  • Proteasome Inhibitors/pharmacology
  • Ubiquitination/drug effects
  • Animals
  • Neurons/metabolism
  • Amyloid beta-Protein Precursor/genetics
  • Cognitive Dysfunction/drug therapy
  • Alzheimer Disease/drug therapy
  • Pyrazoles/pharmacology
  • Cell Line, Tumor
  • Proteolysis/drug effects

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