Abstract
Estradiol-17β (E) plays an important role in ovarian follicular development. Evidence indicates that some of the effect of E is mediated by the transmembrane estrogen receptor. In this study, we examined the spatio-temporal expression of recently discovered ERα36 (ESR36), a splice variant of Esr1 and a receptor for non-genomic E signaling, in the hamster ovary during the estrous cycle and the role of gonadotropins and ovarian steroid hormones in ESR36 expression. ESR36 expression was high on estrus (D1∶0900 h) and declined precipitously by proestrus (D4∶0900 h) and remained low up to D4∶1600 h. Immunofluorescence findings corroborated immunoblot findings and revealed that ESR36 was expressed only in the cell membrane of both follicular and non-follicular cells, except the oocytes. Ovarian ESR36 was capable of binding to the E-affinity matrix, and have different molecular weight than that of the ESR1 or GPER. Hypophysectomy (Hx) resulted in a marked decline in ESR36 protein levels. FSH and LH, alone or combined, markedly upregulated ESR36 protein in Hx hamsters to the levels observed in D1 hamsters, but neither E nor P had any effect. Inhibition of the gonadotropin surge by phenobarbital treatment on D4∶1100 h attenuated ESR36 expression in D1∶0900 h ovaries, but the decline was restored by either FSH or LH replacement on D4 afternoon. This is the first report to show that ESR36, which is distinct from ESR1 or GPER is expressed in the plasma membrane of ovarian follicular and non-follicular cells, binds to E and its expression is regulated directly by the gonadotropins. In light of our previous findings, the results suggest that ovarian cells contain at least two distinct membrane estrogen receptors, such as GPER and ESR36, and strongly suggest for a non-genomic action of E regulating ovarian follicular functions.
Highlights
Estradiol-17b (E) plays a key role in mammalian folliculogenesis [1,2]
Estrogen Receptor a 36 (ESR36) was detected in the granulosa (GC), thecal (Th) as well interstitial cells (IC), cell-type specific expression was apparent (Fig. 1)
At D3:0900h, robust ESR36 expression was evident in the mural granulosa cells of antral follicles; the intensity was somewhat low in the antral granulosa cells as well as in thecal cells (Th) (Fig. 1B)
Summary
Estradiol-17b (E) plays a key role in mammalian folliculogenesis [1,2]. E stimulates the formation of gap junctions [3] and proliferation of granulosa cells (GC), and enhances the action of FSH and LH in the ovary [4]. The genomic action of E is mediated by classic estrogen receptor a (ESR1) and estrogen receptor b (ESR2). AERKO mice are acyclic and infertile with hemorrhagic and cystic antral follicles. Membrane estrogen receptors have been shown to activate different signaling pathways, such as adenylate cyclase [15], phospholipase C (PKC) [16] or mitogen activated protein kinase (MAPK) [17]. Membrane localized ESR1, ESR2 or G-protein coupled estrogen receptor 30 (GPER) has been shown to transduce estrogen signaling in cancer and murine ovarian cells [18,19,20]. A shorter variant of ESR1, ESR36 has been shown to mediate the non-genomic estrogen signaling in breast cancer cell lines [21,22]
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