RT Journal Article
SR Electronic
T1 Membrane Estrogen Receptors Stimulate Intracellular Calcium Release and Progesterone Synthesis in Hypothalamic Astrocytes
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12950
OP 12957
DO 10.1523/JNEUROSCI.1158-10.2010
VO 30
IS 39
A1 John Kuo
A1 Naheed Hamid
A1 Galyna Bondar
A1 Eric R. Prossnitz
A1 Paul Micevych
YR 2010
UL http://www.jneurosci.org/content/30/39/12950.abstract
AB In hypothalamic astrocytes obtained from adult female rats, estradiol rapidly increased free cytoplasmic calcium concentrations ([Ca2+]i) that facilitate progesterone synthesis. The present study demonstrated that estradiol (1 nm) significantly and maximally stimulated progesterone synthesis within 5 min, supporting a rapid, nongenomic mechanism. The group I metabotropic glutamate receptor (mGluR1a) antagonist LY 367385 [(S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid] attenuated both the estradiol-induced [Ca2+]i release and progesterone synthesis. To investigate membrane-associated estrogen receptors (mERs), agonists for ERα, ERβ, STX-activated protein, and GPR30 were compared. The selective ERα agonist propylpyrazole triole (PPT) and STX most closely mimicked the estradiol-induced [Ca2+]i responses, where PPT was more potent but less efficacious than STX. Only high doses (100 nm) of selective ERβ agonist diarylpropionitrile (DPN) and GPR30 agonist G-1 induced estradiol-like [Ca2+]i responses. With the exception of DPN (even at 100 nm), all agonists stimulated progesterone synthesis. The PPT- and STX-induced [Ca2+]i release and progesterone synthesis were blocked by LY 367385. While the G-1-stimulated [Ca2+]i release was blocked by LY 367385, progesterone synthesis was not. Since GPR30 was detected intracellularly but not in the membrane, we interpreted these results to suggest that G-1 could activate mGluR1a on the membrane and GPR30 on the smooth endoplasmic reticulum to release intracellular calcium. Although STX and G-1 maximally stimulated [Ca2+]i release in astrocytes from estrogen receptor-α knock-out (ERKO) mice, estradiol in vivo did not stimulate progesterone synthesis in the ERKO mice. Together, these results indicate that mERα is mainly responsible for the rapid, membrane-initiated estradiol-signaling that leads to progesterone synthesis in hypothalamic astrocytes.