ArticleAging cell2019
Estrogen receptor α promotes Cav1.2 ubiquitination and degradation in neuronal cells and in APP/PS1 mice.
Article in Aging cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 3 of them syntheses that pooled it.
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Who cites it
29 citing papers in PubMed, 3 syntheses or guidelines pooled it, 46 citations in OpenAlex.
- Research progress in estrogen as an adjunctive therapy for schizophrenia.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2024Pooled it
- Comparison of Antioxidant Capacity and Network Pharmacology of Phloretin and Phlorizin against Neuroinflammation in Traumatic Brain Injury.Molecules (Basel, Switzerland) · 2023Pooled it
- The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.Molecular neurobiology · 2023Pooled it
- Beyond Estrogen: Unraveling the Complexities of Hormonal Signaling Pathways in Alzheimer's Disease and Their Implications for Precision Therapy.Molecular neurobiology · 2025Review
- Degradation of voltage-gated calcium channels: mechanisms and applications in neurological and cardiovascular diseases.Cell communication and signaling : CCS · 2025Review
- ELK1 inhibition alleviates amyloid pathology and memory decline by promoting the SYVN1-mediated ubiquitination and degradation of PS1 in Alzheimer's disease.Experimental & molecular medicine · 2025Article
- ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease.Biology of sex differences · 2025Article
- Identification of E3 Ubiquitin Ligase Substrates Using Biotin Ligase-Based Proximity Labeling Approaches.Biomedicines · 2025Review
- Remote Ischemia Postconditioning Mitigates Hippocampal Neuron Impairment by Modulating Cav1.2-CaMKIIα-Aromatase Signaling After Global Cerebral Ischemia in Ovariectomized Rats.Molecular neurobiology · 2024Article
- Protein modification in neurodegenerative diseases.MedComm · 2024Review
- SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- CNature communications · 2023Article
- Caldendrin represses neurite regeneration and growth in dorsal root ganglion neurons.Scientific reports · 2023Article
- Temperament traits mediate the relationship between CACNA1C polymorphisms and bipolar disorder in cisgender women.European archives of psychiatry and clinical neuroscience · 2023Article
- Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future.Frontiers in pharmacology · 2023Review
- Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.Frontiers in cell and developmental biology · 2023Article
- Review
- Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation.Molecular medicine (Cambridge, Mass.) · 2022Article
- Targeting the non-classical estrogen pathway in neurodegenerative diseases and brain injury disorders.Frontiers in endocrinology · 2022Review
- Estrogen receptors and the aging brain.Essays in biochemistry · 2021Review
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.