Caveolin proteins are essential for distinct effects of membrane estrogen receptors in neurons

It has become widely accepted that along with its ability to directly regulate gene expression, estradiol also influences cell signaling and brain function via rapid membrane-initiated events. Many of these novel signaling processes are dependent on estrogen receptors (ERs) localized to the neuronal membrane. However, the mechanism(s) by which ERs are able to trigger cell signaling when targeted to the neuronal membrane surface has yet to be determined. In hippocampal neurons, we find that caveolin proteins are essential for the regulation of CREB (cAMP response element-binding protein) phosphorylation after estradiol activation of metabotropic glutamate receptor (mGluR) signaling. Furthermore, caveolin-1 (CAV1) and CAV3 differentially regulate the ability of estradiol to activate two discrete signaling pathways. ERα activation of mGluR1a is dependent on CAV1, whereas CAV3 is necessary for ERα and ERβ activation of mGluR2/3. These results are consistent with previous reports in non-neuronal cells, implicating the importance of caveolin proteins in rapid estrogen signaling. In addition, the functional isolation of distinct estrogen-sensitive signaling pathways by different caveolin proteins suggests novel mechanisms through which the membrane-initiated effects of estradiol are orchestrated.