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

Aging Cell. 2019 Aug;18(4):e12961. doi: 10.1111/acel.12961. Epub 2019 Apr 22.


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.

Keywords: Alzheimer’s disease; Cav1.2; Estrogen receptor α; K29; Mdm2; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • APP protein, mouse
  • Amyloid beta-Protein Precursor
  • Calcium Channels, L-Type
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • L-type calcium channel alpha(1C)
  • Leupeptins
  • Oligopeptides
  • PS1 antigen
  • Phenols
  • Proteasome Inhibitors
  • Pyrazoles
  • Ubiquitin
  • 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
  • Estradiol
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde