In vivo effects of a GPR30 antagonist.
Estrogen is central to many physiological processes throughout the human body. We have previously shown that the G protein-coupled receptor GPR30 (also known as GPER), in addition to classical nuclear estrogen receptors (ER and ER), activates cellular signaling pathways in response to estrogen. In order to distinguish between the actions of classical estrogen receptors and GPR30, we have previously characterized G-1 (1), a selective agonist of GPR30. To complement the pharmacological properties of G-1, we sought to identify an antagonist of GPR30 that displays similar selectivity against the classical estrogen receptors. Here we describe the identification and characterization of G15 (2), a G-1 analog that binds to GPR30 with high affinity and acts as an antagonist of estrogen signaling through GPR30. In vivo administration of G15 revealed that GPR30 contributes to both uterine and neurological responses initiated by estrogen. The identification of this antagonist will accelerate the evaluation of the roles of GPR30 in human physiology.
Dennis
Megan K
MK
Department of Cell Biology & Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
Burai
Ritwik
R
Ramesh
Chinnasamy
C
Petrie
Whitney K
WK
Alcon
Sara N
SN
Nayak
Tapan K
TK
Bologa
Cristian G
CG
Leitao
Andrei
A
Brailoiu
Eugen
E
Deliu
Elena
E
Dun
Nae J
NJ
Sklar
Larry A
LA
Hathaway
Helen J
HJ
Arterburn
Jeffrey B
JB
Oprea
Tudor I
TI
Prossnitz
Eric R
ER
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019906:Nuclear Magnetic Resonance, Biomolecular; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction
D004967:Estrogens; C109584:GPER1 protein, human; D008024:Ligands; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled