TDAG8活化後經由PKA與PKCε增強辣椒素受體的敏感度; TDAG8 activation sensitizes TRPV1 by PKA- and PKCε-dependent pathways

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Title:	TDAG8活化後經由PKA與PKCε增強辣椒素受體的敏感度;TDAG8 activation sensitizes TRPV1 by PKA- and PKCε-dependent pathways
Authors:	張雁晴;Yen-ching Chang
Contributors:	生命科學研究所
Keywords:	辣椒素受體;T細胞死亡相關受體8;蛋白質激脢A;蛋白質激脢Cε;發炎性疼痛;組織酸化;inflammatory pain;tissue acidosis;TDAG8;PKCε;TRPV1;PKA
Date:	2011-12-28
Issue Date:	2012-01-05 14:28:59 (UTC+8)
Abstract:	在慢性發炎中，高濃度的氫離子在局部組織中累積（組織酸化）引起疼痛。疼痛的強度則與組織酸化的程度相關。組織酸化引起的疼痛主要是經由直接地激活傷害感覺性感覺神經元（nociceptive sensory neurons），或經由酸敏感的受體間接地調節。辣椒素受體（TRPV1）是一個酸敏感的離子通道，在發炎後的背根神經（dorsal root ganglion）節當中，TRPV1基因的表現量與功能增加因而參與發炎性疼痛的產生。近期的研究中發現，酸敏感的G蛋白偶合受體TDAG8，在發炎後的背根神經節中的基因表現量也增加；並且，活化後的TDAG8可以增強TRPV1的敏感度。然而，活化的TDAG8是如何增強TRPV1的敏感度目前仍不清楚。因此，本篇論文主要目的為釐清（1）TDAG8增強TRPV1敏感度的機制與（2）在背根神經節當中，經由酸化或慢性發炎增強TRPV1敏感度的機制。在本篇論文中，我證實經由酸活化後的TDAG8可經由PKA與PKCε兩種激脢增強TRPV1的敏感度。在TDAG8表現的細胞中，TDAG8可經活化Gs蛋白，逕而藉由PKA與PKCε增強TRPV1的敏感度。特別的是，在小於pH 6.0的酸刺激下，TDAG8亦可經由能受到PTX與U73122所抑制的訊息傳導路徑增強TRPV1的敏感度。在培養的背根神經節細胞中，特別是IB4-positive細胞，pH 6.8的酸化可以經由PKA增加TRPV1的敏感度，也確實可以引起PKA與PKCε的活化並且轉移到細胞膜上。進一步研究結果指出，CFA所引起長時間性發炎也可經由PKCε增強TRPV1敏感度。因此，依據不同的情況下，PKA與PKCε皆可增強辣椒素TRPV1的敏感度。 High local proton concentrations (tissue acidosis) found in some chronic inflammation complaints cause painfulness. The degree of associated pain is well correlated with magnitude of acidification. This is attributable to direct excitation of nociceptive sensory neurons or indirect modulation by proton-sensing receptors. Transient receptor potential vanilloid 1 (TRPV1), a proton-sensing ion channel, is involved in inflammatory pain because TRPV1 gene expression is increased and its function is enhanced in inflamed dorsal root ganglion (DRG) neurons. It is recently found that a proton-sensing G-protein-coupled receptors, TDAG8, has increased expression in inflamed DRG and its activation can enhance TRPV1 function. However, it remains unclear how TDAG8 activation sensitizes TRPV1 function. This thesis is to elucidate (1) the mechanism of TDAG8-mediated TRPV1 sensitization, and (2) the acidification- and chronic inflammation-induced TRPV1 sensitization in DRG neurons. I have demonstrated that TDAG8 responds proton to sensitize TRPV1 through PKA- and PKCε-dependent pathways. In TDAG8-expressing cells, TDAG8 can activate Gs protein and then activate PKA or PKCε to sensitize TRPV1. Interestingly, at pH <6.0, TDAG8 can also sensitize TRPV1 through PTX- and U73122-sensitive pathways. In cultured DRG neurons, mild acidification (pH 6.8) induced TRPV1 sensitization through PKA-dependent pathways in IB4-positive neurons, although acidification induced PKA and PKCε translocation. Further studies revealed that CFA-induced long-term inflammation leading to TRPV1 sensitization through PKCε-dependent pathway. Accordingly, PKA and PKCε are involved in TRPV1 sensitization based on different situations.
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