CFTR‐dependent signaling cascade in estrogen biosynthesis

Estrogens play important roles in a wide range of physiological and pathological processes. They are synthesized from androgen and their biosynthesis are profoundly influenced by follicle stimulating hormone (FSH). Abnormal estrogen to androgen ratio are often seen in cystic fibrosis (CF), a common genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), suggesting an involvement of CFTR in regulation of estrogen production. Here we provide evidence demonstrating a role of CFTR in regulation of ovarian estrogen biosynthsis in mouse granulosa cells involving a HCO 3 − sensor, the soluble adenylyl cyclase (sAC). Both CFTR and sAC are shown to be expressed in mouse granulosa cells. Intracellular pH measurement shows that CFTR is involved in HCO 3 − transport. Extracellular HCO 3 − is shown to increase sAC‐dependent cAMP level, enhance basal and FSH‐stimulated CREB phosphorylation, aromatase expression and estradiol production in granulosa cells, which can be significantly reduced by CFTR inhibitor. Reduced aromatase expression and basal and FSH‐stimulated estradiol production are also observed in granulosa cells from cftr knockout/mutant mice. The present results reveal a previously undefined role of CFTR in the regulation of estrogen production by amplifying the signal of FSH through a HCO 3 − /sAC‐dependent cAMP‐CREB pathway. The work was supported by the National 973 projects and the Focused Investment Scheme of CUHK.