Dehydroepiandrosterone-binding proteins (no single canonical receptor exists)

Dehydroepiandrosterone (DHEA) is an abundant endogenous steroid hormone produced primarily in the adrenal zona reticularis, gonads, and brain, serving mainly as a precursor to potent androgens like testosterone and estrogens like estradiol through peripheral metabolism. Unlike dedicated receptors for these sex steroids, DHEA lacks a single high-affinity receptor and instead exerts effects via low-affinity binding to multiple targets, including nuclear androgen receptor (AR), estrogen receptors (ERα/ERβ), G protein-coupled estrogen receptor (GPER1), and membrane receptors such as GABA_A, NMDA, and sigma-1 in the nervous system. It also modulates ion channels (e.g., voltage-gated sodium/calcium, TRPM3), nuclear receptors like PPARα and CAR indirectly, and inhibits glucose-6-phosphate dehydrogenase (G6PDH), influencing NADPH levels and inflammation. Physiologically, DHEA supports signal transduction, neuroprotection, and neurotrophic effects via TrkC binding, with circulating levels declining with age. In disease, altered DHEA levels associate with cancer, neurodegeneration, cardiovascular issues, and metabolic disorders, though therapeutic supplementation with prasterone shows mixed results due to its indirect actions and conversion to active hormones, raising concerns for endocrine disruption.

Other names

DHEA-binding proteinsDHEA receptors (non-specific)membrane DHEA-binding sites

Weak partial agonist at androgen receptor (AR) and estrogen receptors (ERα, ERβ); allosteric modulation of GABA_A, NMDA, sigma-1 receptors; activation of GPER1, PPARα, CAR; precursor to testosterone and estradiol; inhibition of G6PDH