TY - JOUR
T1 - Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor
AU - Qiu, Jian
AU - Rønnekleiv, Oline K.
AU - Kelly, Martin J.
N1 - Funding Information:
The work from the author's laboratories was supported by PHS grants: NS43330, NS38809 and DK68098. GPR30 knock-out mouse breeders were provided by I. Jack Magrisso and Jan S. Rosenbaum, Procter & Gamble Pharmaceuticals, Cincinnati, OH.
PY - 2008/10
Y1 - 2008/10
N2 - Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation and motivated behaviors. The actions of 17β-estradiol (E2) in the brain have been attributed to the activation of estrogen receptors α and β, as well as G-protein-coupled or other membrane-associated estrogen receptors. Recently, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABAB receptors in guinea pig and mouse hypothalamic neurons including proopiomelanocortin (POMC) neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Gαq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182,780-sensitive manner in both guinea pig and mouse neurons. Both E2 and STX are fully efficacious in estrogen receptor α, β knock-out mice. Finally, we observed that the putative membrane-associated estrogen receptor is different from GPR30 in arcuate neurons using whole-cell patch recording in hypothalamic slices from GPR30 knock-out mice. Collectively, these findings suggest that the mER is distinct from ERα, ERβ or GPR30.
AB - Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation and motivated behaviors. The actions of 17β-estradiol (E2) in the brain have been attributed to the activation of estrogen receptors α and β, as well as G-protein-coupled or other membrane-associated estrogen receptors. Recently, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABAB receptors in guinea pig and mouse hypothalamic neurons including proopiomelanocortin (POMC) neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Gαq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182,780-sensitive manner in both guinea pig and mouse neurons. Both E2 and STX are fully efficacious in estrogen receptor α, β knock-out mice. Finally, we observed that the putative membrane-associated estrogen receptor is different from GPR30 in arcuate neurons using whole-cell patch recording in hypothalamic slices from GPR30 knock-out mice. Collectively, these findings suggest that the mER is distinct from ERα, ERβ or GPR30.
KW - G-protein-coupled receptor
KW - GABA receptor
KW - GPR30
KW - POMC neurons
KW - Potassium channels
UR - http://www.scopus.com/inward/record.url?scp=44549085299&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44549085299&partnerID=8YFLogxK
U2 - 10.1016/j.steroids.2007.11.008
DO - 10.1016/j.steroids.2007.11.008
M3 - Article
C2 - 18342349
AN - SCOPUS:44549085299
SN - 0039-128X
VL - 73
SP - 985
EP - 991
JO - Steroids
JF - Steroids
IS - 9-10
ER -