ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Dev Cell. 2018 Nov 5;47(3):294–305.e7.

Steroid hormones were believed to enter target cells via passive diffusion through the plasma membrane. This article shows that, at least for Drosophila, steroid hormones require a protein transporter to enter cells.

Genomic functions of steroid hormones are mediated by intracellular nuclear receptors, which regulate the transcription of target genes in the nucleus upon binding of steroid ligands. It is widely accepted that lipophilic steroid hormones can freely enter and exit cells by simple diffusion across lipid bilayers. In insects, the primary steroid hormone ecdysone enters its target cells and binds to the ecdysone receptor (EcR), which forms a heterodimer with another nuclear receptor Ultraspiracle and activates transcription of multiple genes. The same group of researchers has shown that in Drosophila ecdysone is released from an endocrine gland against the concentration gradient through a vesicle-mediated process, not by simple diffusion. Thus, insect steroid hormone ecdysone requires a membrane transporter to enter cells.

Here, they identify and characterize a Drosophila solute carrier (SLC) transporter, which they named Ecdysone Importer (EcI), involved in cellular uptake of ecdysone. EcI is highly conserved among insects and other arthropods that utilize ecdysteroids, and its tagged protein localizes to the plasma membrane of the cells in tissues that receive ecdysone.

Transporter-mediated steroid hormone trafficking across cell membranes have been demonstrated in many biological systems against their concentration gradient, such as when cells actively eliminate steroid hormones out of the cytoplasm. Such active transport necessarily requires energy, which is often provided by ABC transporters that can couple ATP hydrolysis to substrate transfer.

Collectively, these results challenge the simple diffusion model of ecdysteroid transport across cell membranes, and instead suggest a transporter-mediated, facilitated diffusion mechanism. Evolutionary conservation of solute carrier organic anion (SLCO) superfamily in metazoans may call for a reconsideration of the simple diffusion model of steroid hormone transport beyond arthropods. If these transporters are found in humans, it will represent a paradigm shift in endocrinology. It would also open up the possibility of developing chemical reagents that manipulate steroid hormone entry into cells.