title: Estradiol and tamoxifen differentially regulate a plasmalemmal voltage-dependent anion channel involved in amyloid-beta induced neurotoxicity.
abstract: There is a wealth of information indicating that estradiol exerts rapid actions involved in neuroprotection and cognitive-enhancing effects. Some of these effects appear to delay onset, or even ameliorate, the neuropathology of Alzheimer's disease (AD), although some controversy exists about the beneficial brain effects of estrogen therapies. Therefore, it is crucial to better understand the mechanisms developed by 17β-estradiol to signal in the brain. At the neuronal membrane, the hormone can rapidly interact with estrogen receptors (mERs) or activate other receptors, such as G protein-coupled and ionotropic receptors. And the list of membrane signalling molecules modulated by estradiol in neurons is increasing. VDAC is a voltage-dependent anion channel, known as a mitochondrial porin which is also found at the neuronal membrane, where it appears to be involved in redox regulation, extrinsic apoptosis and amyloid beta neurotoxicity. Moreover, VDAC is present in neuronal lipid rafts, where it is associated with estrogen receptor α-like (mER), forming part of a macromolecular complex together with caveolin-1 and other signalling proteins related to neuronal preservation. Interestingly, we have recently found that 17β-estradiol rapidly promotes VDAC phosphorylation through the activation of protein kinase A (PKA) and Src-kinase, which may be relevant to maintain this channel inactivated. On the contrary, tamoxifen, a selective estrogen receptor modulator (SERM), provokes the dephosphorylation of VDAC, and eventually its opening, by activating a cascade of phosphatases, including protein phosphatase 2 (PP2A). This review will focus on the relevance of these novel findings in the alternative estrogen mechanisms to achieve neuroprotection related to AD.
authors.affiliation: Laboratory of Cellular Neurobiology, Department of Physiology & Institute of Biomedical Technologies, University of La Laguna, School of Medicine, Santa Cruz de Tenerife, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Herrera
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fernandez
authors.forename: Mario
authors.initials: M
authors.lastname: Diaz
authors.forename: Debora
authors.initials: D
authors.lastname: Cury
authors.forename: Raquel
authors.initials: R
authors.lastname: Marin
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004958:Estradiol / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D004967:Estrogens / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004967:Estrogens; D018696:Neuroprotective Agents; D020845:Selective Estrogen Receptor Modulators; D050994:Voltage-Dependent Anion Channels; D013629:Tamoxifen; D004958:Estradiol; D054648:Protein Phosphatase 2