De Roo Mathias, Rodeau Jean-Luc, Schlichter Rémy
Laboratoire de Neurophysiologie Cellulaire et Intégrée, UMR 7519-CNRS, Université Louis Pasteur, 21 rue René Descartes, 67084 Strasbourg Cedex, France.
J Physiol. 2003 Oct 1;552(Pt 1):59-71. doi: 10.1113/jphysiol.2003.046078. Epub 2003 Jul 4.
We have studied the modulatory effect of dehydroepiandrosterone (DHEA), the most abundant neurosteroid produced by glial cells and neurones, on membrane currents induced by the activation of ionotropic ATP (P2X) receptors in neonatal rat dorsal root ganglion neurones. ATP (1 microM) induced three types of currents/responses termed F (fast and transient), S (slowly desensitizing) and M (mixed, sum of F- and S-type responses). DHEA (10 nM to 100 microM) concentration-dependently increased the amplitude of plateau-like currents of S- and M-type responses evoked by submaximal (1 microM) but not saturating (100 microM or 1 mM) concentrations of ATP. Alphabeta-methylene ATP (alphabetame-ATP, 5 microM) also evoked F-, S- and M-type responses, the plateau phases of which were potentiated by lowering external pH (6.3) and by ivermectin (IVM, 3 microM), indicating the presence heteromeric P2X2-containing receptors and possibly of functional native P2X4/6 receptors. There was a strict correlation between the potentiating effects of low pH and DHEA on alphabetame-ATP responses but not between that of IVM and DHEA, suggesting that DHEA selectively modulated P2X2-containing receptors. DHEA also potentiated putative homomeric P2X2 receptor responses recorded in the continuous presence of 1 microM 2'-(or 3')-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP). Our results constitute the first demonstration of a fast potentiation of P2X receptors by a neurosteroid and suggest that DHEA could be an endogenous modulator of P2X2-containing receptors thereby contributing to the facilitation of the detection and/or the transmission of nociceptive messages, particularly under conditions of inflammatory pain where the P2X receptor signalling pathway appears to be upregulated.
我们研究了脱氢表雄酮（DHEA），这种由神经胶质细胞和神经元产生的含量最为丰富的神经甾体，对新生大鼠背根神经节神经元中离子型ATP（P2X）受体激活所诱导的膜电流的调节作用。ATP（1微摩尔）可诱导出三种类型的电流/反应，分别称为F型（快速且短暂）、S型（缓慢脱敏）和M型（混合型，F型和S型反应之和）。DHEA（10纳摩尔至100微摩尔）呈浓度依赖性地增加了由亚最大浓度（1微摩尔）而非饱和浓度（100微摩尔或1毫摩尔）的ATP所诱发的S型和M型反应的平台样电流幅度。αβ-亚甲基ATP（αβme-ATP，5微摩尔）也可诱发F型、S型和M型反应，降低细胞外pH（6.3）以及使用伊维菌素（IVM，3微摩尔）可增强其平台期，这表明存在含P2X2的异聚体受体以及可能存在功能性的天然P2X4/6受体。低pH和DHEA对αβme-ATP反应的增强作用之间存在严格的相关性，但IVM和DHEA之间则不存在，这表明DHEA选择性地调节含P2X2的受体。在持续存在1微摩尔2'-(或3')-O-(2,4,6-三硝基苯基)腺苷5'-三磷酸（TNP-ATP）的情况下，DHEA也增强了所记录的假定的同聚体P2X2受体反应。我们的结果首次证明了神经甾体对P2X受体的快速增强作用，并表明DHEA可能是含P2X2受体的内源性调节剂，从而有助于促进伤害性信息的检测和/或传递，特别是在炎症性疼痛的情况下，此时P2X受体信号通路似乎被上调。
