TY - JOUR
T1 - Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)
AU - Kelly, Martin J.
AU - Qiu, Jian
AU - Wagner, Edward J.
AU - Rønnekleiv, Oline K.
N1 - Funding Information:
The experiments described in this review were supported by US Public Health Service Grants NS 35944, NS 38809, DA 05158 and DA 00192 (Research Scientist Development Award to MJK). The authors would like to recognize Ms. Martha, A. Bosch and Mr. Barry R. Naylor for their expert technical contributions to these studies.
PY - 2002/12
Y1 - 2002/12
N2 - Estrogen rapidly alters the excitability of hypothalamic neurons that are involved in regulating numerous homeostatic functions including reproduction, stress responses, feeding and motivated behaviors. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca2+-activated K+ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K + (GIRK) channels in POMC neurons and GABAB receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24h following steroid administration in vivo, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α 1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.
AB - Estrogen rapidly alters the excitability of hypothalamic neurons that are involved in regulating numerous homeostatic functions including reproduction, stress responses, feeding and motivated behaviors. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca2+-activated K+ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K + (GIRK) channels in POMC neurons and GABAB receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24h following steroid administration in vivo, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α 1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.
KW - Dopamine
KW - GABA
KW - K channel
KW - Norepinephrine
KW - POMC
KW - Protein kinase
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U2 - 10.1016/S0960-0760(02)00249-2
DO - 10.1016/S0960-0760(02)00249-2
M3 - Article
C2 - 12650715
AN - SCOPUS:0037643398
SN - 0960-0760
VL - 83
SP - 187
EP - 193
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1-5
ER -