title: Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor.
abstract: 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 17beta-estradiol (E(2)) in the brain have been attributed to the activation of estrogen receptors alpha and beta, 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 GABA(B) receptors in guinea pig and mouse hypothalamic neurons including proopiomelanocortin (POMC) neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Galphaq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E(2) in mediating this desensitization in an ICI 182,780-sensitive manner in both guinea pig and mouse neurons. Both E(2) and STX are fully efficacious in estrogen receptor alpha, beta 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 ERalpha, ERbeta or GPR30.
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, United States. qiuj@ohsu.edu
authors.forename: Jian
authors.initials: J
authors.lastname: Qiu
authors.forename: Oline K
authors.initials: OK
authors.lastname: Rønnekleiv
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006168:Guinea Pigs; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D011333:Pro-Opiomelanocortin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases