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 language | English |
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Article number | e12961 |
Journal | Aging Cell |
Volume | 18 |
Issue number | 4 |
DOIs | |
State | Published - 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