Mutation of aspartic acid 262 on estrogen receptor abrogates estradiol signaling pathway.

Xingyan Xu, Haowei Yu, Shuihao Zhu, Ping Li, Xiaosa Li, Yongqi Gao, Yixiao Xiang, Guojun Zhao, Tommaso Simoncini, Huiping Lin

Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2023 Dec

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ERα (estrogen receptor alpha) exerts nuclear genomic actions and membrane-initiated non-genomic effects. The mutation of aspartic acid into alanine in vitro revealed the critical role of aspartic acid 258 (corresponding to mouse amino acid site 262) of ERα for non-nuclear function. Our previous in vitro study revealed that this mutation blocked estrogen's non-genomic effects on vascular endothelial H2S release. Here, we studied the in vivo role of the aspartic acid 262 of ERα in the reproductive system and in the vascular tissue. We generated a mouse model harboring a point mutation of the murine counterpart of this aspartic acid into alanine (ERαD262A). Our results showed that the ERαD262A females are fertile with standard hormonal serum levels, but the uterine development and responded with estrogen and follicular development are disrupted. In line with our previous study, we found that the rapid dilation of the aorta was abrogated in ERαD262A mice. In contrast to the previously reported R264-ERα mice, the classical estrogen genomic effector SP1/NOS3/AP1 and the nongenomic effectors p-eNOs, p-AKT, and p-ERK were disturbed in the ERαD262A aorta. Besides, the serum H2S concentration was decreased in ERαD262A mice. Together, ERαD262A mice showed compromised both genomic and non-genomic actions in response to E2. These data showed that aspartic acid 262 of ERα are important for both genomic and non-genomic effects of E2. Our data provide a theoretical basis for further selecting an effective non-genomic mouse model and provide a new direction for developing estrogen non-genomic effect inhibitors.

Citation

Xingyan Xu, Haowei Yu, Shuihao Zhu, Ping Li, Xiaosa Li, Yongqi Gao, Yixiao Xiang, Guojun Zhao, Tommaso Simoncini, Huiping Lin. Mutation of aspartic acid 262 on estrogen receptor abrogates estradiol signaling pathway. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2023 Dec;39(1):2250881