In:
Journal of Neuroendocrinology, Wiley, Vol. 31, No. 6 ( 2019-06)
Abstract:
The two isoforms of the nuclear estrogen receptor, ER α and ER β are widely expressed in the central nervous system. Although they were first described as nuclear receptors, both isoforms have also been found at the cell membrane where they mediate cell signaling. Surface biotinylation studies using neuronal and glial primary cultures label an alternatively spliced form of ER α. The 52 kD a protein, ER αΔ4, is missing exon 4 and is highly expressed in membrane fractions derived from cultured cells. In vivo, both full‐length (66 kD a) ER α and ER αΔ4 are present in membrane fractions. In response to estradiol, full‐length ER α and ER αΔ4 are initially trafficked to the membrane, and then internalized in parallel. Previous studies determined that only the full‐length ER α associates with metabotropic glutamate receptor‐1a ( mG luR1a), initiating cellular signaling. The role of ER αΔ4, remained to be elucidated. Here, we report ER αΔ4 trafficking, association with mG luR2/3, and downstream signaling in female rat arcuate nucleus ( ARH ). Caveolin ( CAV ) proteins are needed for ER transport to the cell membrane, and using co‐immunoprecipitation CAV ‐3 was shown to associate with ER αΔ4. CAV ‐3 was necessary for ER αΔ4 trafficking to the membrane: in the ARH , microinjection of CAV ‐3 si RNA reduced CAV ‐3 and ER αΔ4a in membrane fractions by 50%, and 60%, respectively. Moreover, co‐immunoprecipitation revealed that ER αΔ4 associated with inhibitory mG luRs, mG luR2/3. Estrogen benzoate ( EB ) treatment (5 μg; s.c.; every 4 days; three cycles) reduced levels of cAMP , an effect attenuated by antagonizing mG luR2/3. Following EB treatment, membrane levels of ER αΔ4 and mG luR2/3 were reduced implying ligand‐induced internalization. These results implicate ER αΔ4 in an estradiol‐induced inhibitory cell signaling in the ARH.
Type of Medium:
Online Resource
ISSN:
0953-8194
,
1365-2826
DOI:
10.1111/jne.2019.31.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2007386-0
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