Neuromedin B Drives Goat Granulosa Cell Proliferation via NMBR-Mediated Calcium Homeostasis

Background Neuromedin B (NMB) has been implicated in the regulation of female reproductive functions, yet its precise role and underlying mechanisms in ovarian follicular development remain undefined. Granulosa cells (GCs), the principal functional cells within ovarian follicles, directly govern follicular growth and maturation through their proliferation and differentiation. In this study, we explored the regulatory effects and molecular mechanisms of NMB and its receptor (NMBR) on goat GC proliferation. Results We documented dynamic expression patterns of NMB and NMBR throughout ovarian and follicular development. Exogenous NMB treatment markedly enhanced GC proliferation, as evidenced by an increased fraction of S-phase cells and upregulation of CCNE1 and CDK1/2/6. Mechanistically, NMB bound to NMBR to activate phospholipase C β1 (PLCβ1), triggering endoplasmic reticulum (ER) Ca²⁺ release and significantly raising cytosolic Ca²⁺ levels while alleviating ER stress. Further analyses revealed that NMB strengthened mitochondria-associated ER membranes (MAMs) formation via the IRE1α–IP3R–VDAC1 axis, facilitating Ca²⁺ transfer into mitochondria. This led to enhanced mitochondrial function, including increased mitochondrial membrane potential, elevated respiratory chain complex activities, augmented ATP production, and promotion of mitochondrial network fusion. Importantly, these effects were abolished by an NMBR antagonist. Conclusions The molecular mechanism by which NMB-mediated activation of NMBR enhances mitochondrial metabolism through modulation of intracellular calcium homeostasis, thereby promoting proliferation of goat GCs. These findings shed new light on the regulation of follicular development and may inform strategies to improve reproductive efficiency in goats.