Amplification of FSH signalling by CFTR and nuclear soluble adenylyl cyclase in the ovary

Abstract

Summary The cAMP/PKA pathway is one of the most important signalling pathways widely distributed in most eukaryotic cells. The activation of the canonical cAMP/PKA pathway depends on transmembrane adenylyl cyclase (tmAC). Recently, soluble adenylyl cyclase (sAC), which is activated by HCO3− or Ca2+, emerges to provide an alternative way to activate cAMP/PKA pathway with the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP‐activated Cl−/HCO3−‐conducting anion channel, as a key player. This review summarizes new progress in the investigation of the CFTR/HCO3−‐dependent sAC signalling and its essential role in various reproductive processes, particularly in ovarian functions. We present the evidence for a CFTR/HCO3−‐dependent nuclear sAC signalling cascade that amplifies the FSH‐stimulated cAMP/PKA pathway, traditionally thought to involve tmAC, in granulosa for the regulation of oestrogen production and granulosa cell proliferation. The implication of the CFTR/HCO3−/sAC pathway in amplifying other receptor‐activated cAMP/PKA signalling in a wide variety of cell types and pathophysiological processes, including aging, is also discussed.

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

“…Moreover, CFTR via the sAC-cAMP-PKA pathway has been shown to promote embryo development through the suppression of p53-dependent development arrest [ 93 ]. Taken together, the CFTR-sAC axis seems to play an important role in reproductive processes [ 94 ].…”

A network pharmacological approach to evaluate Jia-Wei-Xiao-Yao-san formula’s mechanistic pathways and its implication in the symptomatology of polycystic ovarian syndrome

“…59 At least in part, the JWXYS formula compounds interact with CYP19A1. The CDT network further indicates the JWXYS formula compounds could participate in modulating FSHR and LHCGR, therefore mimicking the endogenous FSH involved in stimulating the cAMP pathway in granulosa cells which then could regulate estrogen production, 60 through the link activation of CYP19A1-ESR1 ( Figure 4C). Another endocrine pathway shows that LH increases estradiol secretion in preantral follicles through up-regulating CYP17A1 and CYP19A1 gene transcripts in PCOS, 61,62 and reflect those two nodes observed in the CDT network.…”

“…According to population-based studies conducted in Taiwan, patients with uterine bleeding or hypertension received a JWXYS average daily dose of 7.3-7.5g. 37,38 Previous studies pointed out the indications JWXYS to be especially effective for alleviating menopausal symptoms and menstrual disorders. 33,39,[40][41][42] A clinical study indicated the use of JWXYS for improving depression status in menopause patients by increasing serum levels of TNF-alpha after 12weeks of treatment 43 and supported by a retrospective populationbased study that showed JWXYS as the most prescribed formula (12%) for patients having sleep disorders and major depressive disorder.…”

Aging mechanisms and intervention targets

“…Menopause contributes to osteoporosis and visceral adiposity, but management of these disorders has been challenging. Recent studies show that follicle‐stimulating hormone (FSH) signalling is amplified by cystic fibrosis transmembrane conductance regulator (CFTR) and nuclear soluble adenylyl cyclase in granulosa for the regulation of oestrogen production and granulosa cell proliferation (reviewed in Chen). Metabolic disorder in the CFTR/sAC pathway during amplifying other receptor‐activated cAMP/PKA signalling has been suggested to be involved in ovarian aging .…”

“…Recent studies show that follicle‐stimulating hormone (FSH) signalling is amplified by cystic fibrosis transmembrane conductance regulator (CFTR) and nuclear soluble adenylyl cyclase in granulosa for the regulation of oestrogen production and granulosa cell proliferation (reviewed in Chen). Metabolic disorder in the CFTR/sAC pathway during amplifying other receptor‐activated cAMP/PKA signalling has been suggested to be involved in ovarian aging . More recently, a polyclonal antibody targeting the beta‐subunit of the pituitary hormone FSH has been shown to increase bone mass and reduce adipose mass in mice .…”