Division of Molecular Pharmacology and Neuroscience
Nagasaki University Graduate School of Biomedical Sciences
Nagasaki University Center for Pain Research
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Theme 4
Molecular and Cellular Biology of Neurosteroids and Endocrine Disruptors
1. Topics
Neurosteroids are synthesized in the brain and functions as neuromediators. We are interested in new molecular target receptors for neurostroids. One of new targets are the membrane G protein coupled receptors, which are shared with endocrine disruptors. We have reported that some neurosteroids share pharmacological actions with a putative Gi-coupled sigma (s) receptor in the brain through reconstitution experiments (Ueda et al. Neurosci Res 41:33-40, 2001).
Furthermore, we found that pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulfate (DHEAS), two representative neurosteroids, induce nociceptive flexor responses through two novel types of neurosteroid receptors, termed neuronal NS1/s-type and non-neuronal NS2-type (Ueda et al. J. Pharmacol. Exp. Ther. 298, 703-710, 2001). The NS2-type neurosteroid receptor probably exists on mast cells to induce histamine release, since the nociceptive responses and plasma extravasation after neurosteroid stimulation were completely blocked by diphenhydramine (DPH), a histamine antagonist (Ueda et al. J. Pharmacol. Exp. Ther. 298, 703-710, 2001 ; Uchida et al. Neurochem. Int. 42, 401-407, 2003). While studying the physiological and pathophysiological roles of this peripheral neurosteroid receptor, we also found that its neurosteroid- induced actions were abolished by 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE), an endocrine-disrupting chemical (EDC) that possesses estrogenic actions (Uchida et al. Neurochem. Int. 42, 401-407, 2003). Therefore, the peripheral neurosteroid receptor may be a target for some EDCs as well as nuclear steroid receptors. Most recently, we further demonstrate the involvement of the putative Gq/11-coupled neurosteroid receptor in the mast cell degranulation induced by neurosteroids and EDCs (Mizota et al., Br.J.Pharmacol. 2005).
We currently found MAP2, which is involved in the dendritic outgrowth could be also targets for these substances. Our goal is to develop the in vitro and in vivo assay systems to evaluate the risks of neuroactive endocrine disrupting chemicals through molecular identification of such targets.