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研究生(外文):Tsui-Jumg Chang
論文名稱(外文):Mechanism Underlying the Effect of Dehydroepiandrosterone on the Capsaicin Receptor-Mediated Response
指導教授(外文):Fong-Sen Wu
外文關鍵詞:capsaicin receptorDehyroepiandrosterone
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先前的研究顯示,神經性類固醇去氫男性脂酮(DHEA)對分佈在腦部神經細胞膜上之NMDA受體和GABAA受體具有調節的作用。DHEA對胺基酸受體的作用現已被廣泛地研究,但是其對capsaicin受體的作用卻很少有人做研究。在本實驗中,我們採用快速分離出來的成年大白鼠背根神經節細胞為材料,利用全細胞膜電位固定的電生理記錄方法,探討DHEA及相關類固醇對capsaicin受體所媒介電流反應的調控作用。結果顯示DHEA快速且可逆地抑制capsaicin受體所誘發的全細胞內向電流,且其抑制作用呈現濃度依賴效應,最大抑制作用為100 %,而達到最大抑制作用一半所需的DHEA濃度(EC50)為6.7 mM。DHEA對capsaicin所誘發反應的抑制作用隨著capsaicin濃度的增加而遞減,表示DHEA對capsaicin受體所媒介反應的抑制作用是屬於競爭型。Capsaicin所誘發的電流及DHEA抑制capsaicin所誘發電流的能力,並不會因為細胞內液添加飽和濃度DHEA而有所降低,表示DHEA對capsaicin所誘發電流的抑制作用,是經由作用到capsaicin受體的細胞外表面位置來達成的。此外,我們發現,DHEA並不是透過活化去磷酸酶1、2A或2B來抑制capsaicin所誘發的電流。並非所有的類固醇對capsaicin所誘發的反應都有抑制作用。黃體激素對capsaicin所誘發的電流幾乎沒有作用,表示DHEA對capsaicin受體的抑制作用具專一性。此外,DHEA的立體異構物3a-DHEA對capsaicin所誘發的反應不但沒有抑制作用,反而有增強的作用,顯示類固醇對capsaicin受體的調控作用具立體結構專一性。
Previous studies have shown that the neurosteroid dehydroepiandrosterone (5-androsten-3b-ol-17-one; DHEA) modulates N-methyl-D-aspartate (NMDA) receptor- and g-aminobutyric acid type A (GABAA) receptor-mediated responses in brain. Compared to the extensive studies of DHEA effects on amino acid receptors, relatively little is known of interaction of DHEA with the capsaicin receptor. In the present study, we investigated the effects of DHEA and related steroids on the capsaicin receptor-mediated current in acutely dissociated rat dorsal root ganglion neurons using the whole-cell voltage-clamp recording technique. DHEA rapidly and reversibly inhibited the capsaicin-induced current in a concentration-dependent manner, with an EC50 of 6.7 mM and a maximal inhibition of 100 %. Inhibition by DHEA of the capsaicin response was significantly reduced when capsaicin was increased to higher concentrations, indicating that the blocking action of DHEA is competitive. Neither the capsaicin response nor inhibition of the capsaicin response by extracellularly applied DHEA was significantly affected by inclusion of a saturating concentration of DHEA in the electrode buffer, arguing that DHEA acted at the extracellular surface of the membrane. Moreover, DHEA did not act through protein phosphatases 1, 2A or 2B to inhibit the capsaicin-induced current. Not all steroids inhibited the capsaicin response. Progesterone did not exert any significant effect on the capsaicin-induced current, suggesting that inhibition by DHEA of the capsaicin response is a specific effect. Furthermore, the stereoisomer of DHEA, 5-androsten-3a-ol-17-one (3a-DHEA), failed to inhibit the capsaicin-induced current, producing instead a potentiating effect on the capsaicin response, demonstrating that interaction of steroids with the capsaicin receptor is stereospecific.
緒論....................................... 1
材料與方法................................. 4
結果....................................... 16
討論....................................... 34
參考文獻................................... 39
附錄....................................... 49
誌謝....................................... 56
履歷....................................... 57
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