Neuromedin S (NMS) 在生殖调节中发挥着关键作用，但其在卵泡发育中的功能和机制仍不清楚。本研究旨在探讨NMS及其受体在调节卵巢颗粒细胞（GC）增殖和类固醇生成中的具体作用和机制。从表型上看，一定浓度的NMS添加促进了山羊GC的增殖和雌激素的产生，伴随着G1/S细胞群的增加以及细胞周期蛋白D1、细胞周期蛋白依赖性激酶6、类固醇生成急性调节蛋白、细胞色素的表达水平的上调P450，家族 11，亚家族，多肽 1，3β-羟基类固醇脱氢酶和细胞色素 P450，家族 11，亚家族，多肽 1，而 NMS 治疗的效果受到 2 型神经调节素 U 受体 (NMUR2) 敲低的有效阻碍。从机制上讲，用 NMS 激活 NMUR2 通过触发 PLCG1-IP3R 途径维持内质网 (ER) 钙 (Ca2+) 稳态，这有助于保护 ER 形态，维持适当水平的内质网未折叠蛋白反应 (UPRer)，并抑制核激活转录因子 4 的易位。此外，NMS 维持细胞内 Ca2 稳态，以激活钙调蛋白 1-大肿瘤抑制激酶 1 通路，最终通过 Yes1 相关转录调节因子 ATF4-c-Jun 协调山羊 GC 增殖和雌激素产生的调节途径。至关重要的是，NMUR2 基因的同时敲低减轻了 NMS 的影响。总的来说，这些数据表明，NMS 激活 NMUR2 通过调节 ER 和细胞内 Ca2 稳态，增强山羊 GC 中的细胞增殖和雌激素产生，从而激活 YAP1-ATF4-c-Jun 通路。这些发现为卵泡生长和发育的调控机制提供了宝贵的见解，为未来的研究提供了新的视角。© 2024 Wiley periodicals LLC。

Neuromedin S (NMS) plays key roles in reproductive regulation, while its function and mechanism in follicular development remain unclear. The current study aims to investigate the specific role and mechanisms of NMS and its receptors in regulating the proliferation and steroidogenesis of ovarian granulosa cells (GCs). Phenotypically, a certain concentration of NMS addition promoted the proliferation and estrogen production of goat GCs, accompanied by an increase in the G1/S cell population and upregulation of the expression levels of cyclin D1, cyclin dependent kinase 6, steroidogenic acute regulatory protein, cytochrome P450, family 11, subfamily A, polypeptide 1, 3beta-hydroxysteroid dehydrogenase, and cytochrome P450, family 11, subfamily A, polypeptide 1, while the effects of NMS treatment were effectively hindered by knockdown of neuromedin U receptor type 2 (NMUR2). Mechanistically, activation of NMUR2 with NMS maintained endoplasmic reticulum (ER) calcium (Ca2+) homeostasis by triggering the PLCG1-IP3R pathway, which helped preserve ER morphology, sustained an appropriate level of endoplasmic reticulum unfolded protein response (UPRer), and suppressed the nuclear translocation of activating transcription factor 4. Moreover, NMS maintained intracellular Ca2+ homeostasis to activate the calmodulin 1-large tumor suppressor kinase 1 pathway, ultimately orchestrating the regulation of goat GC proliferation and estrogen production through the Yes1 associated transcriptional regulator-ATF4-c-Jun pathway. Crucially, the effects of NMS were mitigated by concurrent knockdown of the NMUR2 gene. Collectively, these data suggest that activation of NMUR2 by NMS enhances cell proliferation and estrogen production in goat GCs through modulating the ER and intracellular Ca2+ homeostasis, leading to activation of the YAP1-ATF4-c-Jun pathway. These findings offer valuable insights into the regulatory mechanisms involved in follicular growth and development, providing a novel perspective for future research.© 2024 Wiley Periodicals LLC.