Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find that mucus released from the murine reproductive tract critically depends upon concurrent bicarbonate (HCO 3 − ) secretion. Prostaglandin E 2 (PGE 2 )-and carbachol-stimulated mucus release was severely inhibited in the absence of serosal HCO 3 − , HCO 3 − transport, or functional cystic fibrosis transmembrane conductance regulator (CFTR). In contrast to mucus release, PGE 2 -and carbachol-stimulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. We found stimulated mucus release was severely impaired in the cystic fibrosis F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced female fertility associated with abnormal mucus and specifically, may account for the increased viscosity and lack of cyclical changes in cervical mucus long noted in women with cystic fibrosis.

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Thyroid hormones (THs) must be taken up by target cells to act at the genomic level through binding to nuclear thyroid hormone receptors (TRs). Extensive study has been made of mechanisms by which TH-bound TRs regulate transcription, yet little is known about the critical upstream step, i.e. how THs enter the cell. Growing evidence suggests that saturable transport mechanisms mediate the greater part of TH movement across the plasma membrane and have important roles in the regulation of TH bioavailability. For example, System L is a multifunctional transport system serving as a plasma membrane transporter of THs and amino acids in mammalian cells. We have used two complementary systems, the Xenopus oocyte (which has negligible basal System L activity) and the mammalian BeWo cell line (which has System L activity for TH transport), to investigate the role of this representative TH transporter in nuclear action of THs. We demonstrate that overexpression of System L in Xenopus oocytes increases both cytoplasmic and nuclear delivery of THs from external medium and also enhances transcriptional activation by TRs. Conversely, blocking endogenous System L activity in BeWo cells with specific inhibitors reduces both TH uptake and TR function. These results indicate that plasma membrane TH transporters such as System L may have important roles in gene regulation by TRs.

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