Category: receptor_pharmacology
Estrogen acts through three receptor classes with distinct kinetics + tissue distribution: (1) ERα (ESR1) — high in uterus, mammary, ovary, hypothalamus, bone, liver; major proliferative + endometrial driver; tamoxifen mixed agonist/antagonist depending on tissue (SERM). (2) ERβ (ESR2) — high in ovary, prostate, lung, vasculature, CNS; often opposes ERα effects in same tissues; potential tumor-suppressive in breast. (3) GPER (G-protein-coupled ER, formerly GPR30) — membrane GPCR responding to estradiol → rapid non-genomic via Gs → cAMP, also via EGFR transactivation → MAPK/PI3K cascade in seconds-minutes. Genomic mechanism (ERα/β): estradiol binds → HSP90 dissociation → homo/heterodimerization → binds ERE (estrogen response element, palindromic) → coactivator recruitment (SRC-1/2/3, p300, AIB1) → transcription. Tethered transcription: ER also activates genes lacking ERE via tethering to AP-1 (Fos/Jun) or Sp1 — tissue-specific basis for SERM selectivity. Non-genomic membrane ER (small pool of ERα/β at membrane via palmitoylation) → rapid PI3K/AKT, MAPK signaling complements genomic. Clinical: post-menopausal HRT (estradiol + progestin) — WHI 2002 raised CV/breast cancer concerns (timing hypothesis nuance); SERMs — tamoxifen (breast: antagonist + endometrium: agonist → ↑endometrial CA risk), raloxifene (osteoporosis: agonist + breast: antagonist + uterus: neutral); SERDs — fulvestrant (full antagonist degrader); aromatase inhibitors (anastrozole/letrozole non-steroidal; exemestane steroidal) — block estradiol synthesis. Cross-links: [[steroid_hormone_biosynthesis]], [[aromatase_androgen_receptor_axis]], [[hpg_axis]], [[mapk_erk_cascade]] (GPER cascade).