The knowledge of the molecular mechanism by which estrogens exert pleiotropic functions in different tissues and organs has evolved rapidly during the past two decades. It is now well established that 17β-estradiol (E2) induces the transcriptional regulation of target gene expression upon binding to the intracellular estrogen receptor-α (ERα) or -β (ERb). In addition E2 modulates cell functions through rapid non-genomic actions. Stimulation of G-proteins, Ca2+ influx as well as phospholipase C, ERK/MAPK, and PI3K/AKT activation occur within seconds to minutes upon E2 binding to a small population of ERα located at the plasma membrane. Several laboratories have recently examined the structural requirements for the localization and function(s) of plasma membrane ERα. We have shown that human ERα location at the plasma membrane and its interaction with caveolin-1 is mediated by S-palmitoylation of the Cys447 residue. Moreover, E2 also modulates Cys447 S-(de)palmitoylation enabling ERα association with signal transduction proteins (e.g. Src and G-proteins) in a cell context-related fashion. This leads to downstream signaling important for cell growth and survival. Here, the structural bases and mechanisms for ERα localization and action(s) are discussed along with potential implications for development of new drugs.
Keywords: Estrogen receptor a, S-palmitoylation, rapid non-genomic effects, plasma membrane location, drug targeting
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