title: Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors.
abstract: Dehydroepiandosterone (DHEA), the most abundant steroid in humans, affects multiple cellular functions of the endocrine, immune, and nervous systems. However, up to quite recently, no receptor has been described specifically for it, whereas most of its physiological actions have been attributed to its conversion to either androgens or estrogens. DHEA interacts and modulate a variety of membrane and intracellular neurotransmitter and steroid receptors. We have recently reported that DHEA protects neuronal cells against apoptosis, interacting with TrkA, the high-affinity prosurvival receptor of the neurotrophin, nerve growth factor. Intrigued by its pleiotropic effects in the nervous system of a variety of species, we have investigated the ability of DHEA to interact with the other two mammalian neurotrophin receptors, ie, the TrkB and TrkC, as well as their invertebrate counterparts (orthologs) in mollusks Lymnaea and Aplysia and in cephalochordate fish Amphioxus. Amazingly, DHEA binds to all Trk receptors, although with lower affinity by 2 orders of magnitude compared with that of the polypeptidic neurotrophins. DHEA effectively induced the first step of the TrkA and TrkC receptors activation (phosphorylation at tyrosine residues), including the vertebrate neurotrophin nonresponding invertebrate Lymnaea and Aplysia receptors. Based on our data, we hypothesize that early in evolution, DHEA may have acted as a nonspecific neurotrophic factor promoting neuronal survival. The interaction of DHEA with all types of neurotrophin receptors offers new insights into the largely unidentified mechanisms of its actions on multiple tissues and organs known to express neurotrophin receptors.
authors.affiliation: Institute of Molecular Biology and Biotechnology (I.P., A.G.), Foundation of Research and Technology-Hellas; and Departments of Pharmacology (I.P., N.D., I.C., A.G.), Biology (I.I., I.T.), and Clinical Chemistry (A.N.M.), School of Medicine, University of Crete, Heraklion 71110, Greece.
authors.forename: Iosif
authors.initials: I
authors.lastname: Pediaditakis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Iliopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Theologidis
authors.forename: Nickoleta
authors.initials: N
authors.lastname: Delivanoglou
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Margioris
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
mesh_terms: D000818:Animals; D003687:Dehydroepiandrosterone / Q000737:chemistry / Q000378:metabolism*; D019143:Evolution, Molecular; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D007448:Invertebrates; D008024:Ligands; D008322:Mammals; D015394:Molecular Structure; D010802:Phylogeny; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*
chemical_list: D008024:Ligands; D017475:Receptors, Nerve Growth Factor; D003687:Dehydroepiandrosterone; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases