Role of the Membrane Estrogen Receptor in Vascular Cell Physiology

Estrogen’s cellular actions are felt to be mediated through response elements on the promoters of target genes, or through modifying transcription via protein-protein interactions (1–4). There is increasing evidence, however, that ligands for various members of the steroid receptor superfamily modulate cell functions via nongenomic actions. Some of these actions appear to originate through plasma membrane protein interactions (5–8). As examples of nongenomic functions, progesterone quickly stimulates increased [Ca2+]i in sperm (6), and aldosterone rapidly activates inositol1,4,5-trisphosphate generation in several cell types (8), or stimulates hemodynamic changes quickly (9). 17β-Estradiol (17βE2) can induce various signal transduction events in seconds to a few minutes. These events include the stimulation of calcium flux (10), cAMP (11), phospholipase C activation, and inositol phosphate generation (12,13), as well as the rapid release of prolactin (14). Many of the rapid actions of 17β-E2 have been attributed to interactions at the cell membrane. These could include 17β-E2 indirectly activating tyrosine kinase growth factor receptors (e.g., epidermal growth factor receptor, EGFR), with subsequent signal transduction initiated through these receptors (15). On the other hand, the existence of a cell membrane estrogen receptor (ER) was reported more than 20 years ago (16).