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2000年 生化学会春季大会要旨

カテゴリー:2. Receptor

Two types of neurosteroid receptors sensitive to sigma ligands or endocrine disruptors

Akira Yoshida and Hiroshi Ueda

We have reported the presence of metabotropic sigma receptor in experiments measuring agonist-stimulated G protein activity of synaptic membranes [1, 2]. From reconstitution experiments the receptor was found to be functionally coupled with G#{i1}, but not G#{oA}. Using similar approaches, neurosteroids such as dehydroepiandrosterone, its sulfate (DHEAS), and pregnenolone sulfate also stimulated [^{35}S]GTP*{g}S binding derived from G#{i1} in reconstitution experiments, and these actions were blocked by progesterone (PROG), another neurosteroid and NE-100, a sigma receptor antagonist. On the other hand, the pentazocine, a sigma receptor agonist stimulated [^{35}S]GTP*{g}S binding and its was blocked by PROG and NE-100. Similar profiles were also observed in @{in vivo} experiments. In the peripheral nociception test in mice, intraplantar injection of SA-4503, a sigma agonist (0.1 to 100 pmol) showed nociceptive responses which were blocked by local application with pertussis toxin (PTX) and by intrathecal pretreatments with antisense oligodeoxynucleotide for G#{i1}. DHEAS in doses of 0.1 amol to 1 fmol caused PTX-insensitive nociception through a histamine release from mast cells, and they were blocked by endocrine disruptors such as stylene dimer, methoxychlor and dichlorodiphenylethylene. On the other hand, DHEAS in doses of 1 pmol to 1 nmol in the presence of diphenhydramine for blockade of the histamine action still showed nociceptive effects which were blocked by NE-100. These findings suggest that there exist novel two types of neurosteroid receptors, neuronal NS1/*{s} type which mediates activation of G#{i1} by neurosteroids and sigma-agonists, and NS2 type which mediates histamine release from mast cells by lower doses of neurosteroids and is blocked by endocrine disruptors.

References

[1] Tokuyama, S., Hirata, K., Ide, A., Ueda, H. (1997) Neurosci. Lett. 233, 141-144.

[2] Tokuyama, S., Hirata, K., Yoshida, A., Maruo, J., Matsuno, K., Mita, S., Ueda, H. (1999) Neurosci. Lett. 268, 85-88.