Estrogen rapidly alters the excitability of hypothalamic neurons that are involved in regulating numerous homeostatic functions including reproduction, stress responses, feeding, and motivated behaviors. Neurosecretory neurons, such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons, such as pro-opiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons, are among those involved. We have identified membrane-initiated, rapid-signaling pathways through which 17β-estradiol (E2) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E2 rapidly uncouples μ-opioid and GABAB receptors from G-protein-gated inwardly rectifying K+ (GIRK) channels in POMC and dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to activate these channels. These effects are mimicked by the selective E2 receptor modulators raloxifene and 4OH-tamoxifen, the membrane impermeable E2-bovine serum albumin (BSA), but not by 17α-estradiol. Furthermore, the anti-estrogen ICI 182,780 antagonizes these rapid effects of E2. Inhibitors of phospholipase C, protein kinase C, and protein kinase A block the actions of E2, indicating that the E2 receptor is G-protein-coupled to activation of this cascade. Conversely, estrogen enhances the efficacy of α1-adrenergic receptor agonists to inhibit apamin-sensitive small-conductance, Ca2+-activated K+ (SK) currents in preoptic GABAergic neurons; it does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate that E2 can modulate K+ channels in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions through multiple intracellular signaling pathways.
- K channel
- Lipase C
- Protein kinase A
- Protein kinase C
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- History and Philosophy of Science