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J. Biol. Chem., Vol. 283, Issue 16, 11064-11071, April 18, 2008

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Prostaglandin E₂ Attenuates Preoptic Expression of GABA_A Receptors via EP3 Receptors^*

Hiroyoshi Tsuchiya¹, Takakazu Oka^¶, Kazuhiro Nakamura^||2, Atsushi Ichikawa, Clifford B. Saper, and Yukihiko Sugimoto³

From the Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences and ^||Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan, Department of Neurology and Program in Neuroscience, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, and ^¶Division of Psychosomatic Medicine, Department of Neurology, University of Occupational and Environmental Health, Iseigaoka 1-1, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

Prostaglandin E₂ (PGE₂) has been shown to produce fever by acting on EP3 receptors within the preoptic area of the brain. However, there is little information about the molecular events downstream of EP3 activation in preoptic neurons. As a first step toward this issue, we examined PGE₂-induced gene expression changes at single-cell resolution in preoptic neurons expressing EP3. Brain sections of the preoptic area from PGE₂- or saline-injected rats were stained with an anti-EP3 antibody, and the cell bodies of EP3-positive neurons were dissected and subjected to RNA amplification procedures. Microarray analysis of the amplified products demonstrated the possibility that gene expression of -aminobutyric acid type A (GABA_A) receptor subunits is decreased upon PGE₂ injection. Indeed, we found that most EP3-positive neurons in the mouse preoptic area are positive for the 2 or 2 GABA_A receptor subunit. Moreover, PGE₂ decreased the preoptic gene expression of these GABA_A subunits via an EP3-dependent and pertussis toxin-sensitive pathway. PGE₂ also attenuated the preoptic protein expression of the 2 subunit in wild-type but not in EP3-deficient mice. These results indicate that PGE₂-EP3 signaling elicits G_i/o activation in preoptic thermocenter neurons, and we propose the possibility that a rapid decrease in preoptic GABA_A expression may be involved in PGE₂-induced fever.

Received for publication, February 20, 2008

^* This work was supported in part by a grant from the Sankyo Foundation of Life Science and by grants-in-aid for scientific research (B) and on priority areas (Applied Genomics, Mechanisms of Sex Differentiation, and Molecular Brain Science) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Ministry of Health and Labor of Japan, respectively. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a research fellowship from the Japan Society for the Promotion of Science for Young Scientists.

² Supported by a fellowship from the Japan Society for the Promotion of Science.

³ To whom correspondence should be addressed: Kyoto University Graduate School of Pharmaceutical Sciences, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Fax: 81-75-753-4557; E-mail: ysugimot{at}pharm.kyoto-u.ac.jp.

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