Estrogen Modulation of G-Protein-Coupled Receptor Activation of Potassium Channels in the Central Nervous System

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 GABA_B 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 GABA_B 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.