| First Author | Lai YJ | Year | 2019 |
| Journal | Aging Cell | Volume | 18 |
| Issue | 4 | Pages | e12961 |
| PubMed ID | 31012223 | Mgi Jnum | J:295829 |
| Mgi Id | MGI:6454560 | Doi | 10.1111/acel.12961 |
| Citation | Lai YJ, et al. (2019) Estrogen receptor alpha promotes Cav1.2 ubiquitination and degradation in neuronal cells and in APP/PS1 mice. Aging Cell 18(4):e12961 |
| abstractText | 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, 17beta-estradiol (E2) reduced Cav1.2 protein through estrogen receptor alpha (ERalpha). 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 ERalpha 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 ERalpha-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 ERalpha agonist PPT reduced cerebral Cav1.2 protein, increased Cav1.2 ubiquitination, and improved cognitive performances. Taken together, ERalpha-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. |
