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 gamma-aminobutyric acid (GABA) neurons, are among those involved. We have identified membrane-initiated, rapid-signaling pathways through which 17beta-estradiol (E(2)) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E(2) rapidly uncouples micro -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 micro -opioid and GABA(B) receptor agonists to activate these channels. These effects are mimicked by the selective E(2) receptor modulators raloxifene and 4OH-tamoxifen, the membrane impermeable E(2)-bovine serum albumin (BSA), but not by 17alpha-estradiol. Furthermore, the anti-estrogen ICI 182,780 antagonizes these rapid effects of E(2). Inhibitors of phospholipase C, protein kinase C, and protein kinase A block the actions of E(2), indicating that the E(2) receptor is G-protein-coupled to activation of this cascade. Conversely, estrogen enhances the efficacy of alpha1-adrenergic receptor agonists to inhibit apamin-sensitive small-conductance, Ca(2+)-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 E(2) can modulate K(+) channels in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions through multiple intracellular signaling pathways.