Chen Xuanmao, Paukert Martin, Kadurin Ivan, Pusch Michael, Gründer Stefan
University of Tübingen, Department of Physiology II, Gmelinstr. 5, 72076 Tübingen, Germany; University of Würzburg, Department of Physiology II, Röntgenring 9, 97070 Würzburg, Germany.
Neuropharmacology. 2006 Jun;50(8):964-74. doi: 10.1016/j.neuropharm.2006.01.007. Epub 2006 Mar 20.
Acid-sensing ion channels are excitatory receptors for extracellular H+. Since the extracellular H+ concentration can significantly increase during an inflammation, one of the proposed functions for ASICs is peripheral perception of pain. The ASIC1b and ASIC3 subunits are specifically expressed in sensory ganglia neurons and are candidate sensors of peripheral acidosis. However, the function of these ASIC subunits is limited by their steady-state desensitization during a small but persistent increase of the H+ concentration and by their desensitization after stronger H+ stimuli. Here we show that ASIC1b and ASIC3 form a heteromeric channel that, at steady-state, desensitizes at more acidic values than either homomeric ASIC1b or homomeric ASIC3 alone. Moreover, we show that RFamide neuropeptides, putative modulators of ASIC activity during inflammation, drastically slow down the desensitization of the ASIC1b/3 heteromer with an apparent dissociation constant of approximately 24microM. The apparent affinity for RFamide-induced effects was about 3-fold higher at low extracellular calcium concentrations. Our results suggest that the ASIC1b/3 heteromer is a possible target for RFamide neuropeptides in the peripheral nervous system.
酸敏感离子通道是细胞外氢离子的兴奋性受体。由于在炎症过程中细胞外氢离子浓度会显著升高，酸敏感离子通道的一个推测功能是对外周疼痛的感知。ASIC1b和ASIC3亚基在感觉神经节神经元中特异性表达，是外周酸中毒的候选感受器。然而，这些ASIC亚基的功能受到限制，即在氢离子浓度小幅但持续升高时它们会发生稳态脱敏，以及在更强的氢离子刺激后也会发生脱敏。在此我们表明，ASIC1b和ASIC3形成一个异源通道，在稳态下，该通道比单独的同型ASIC1b或同型ASIC3在更酸性的值时发生脱敏。此外，我们表明，RFamide神经肽是炎症期间ASIC活性的假定调节剂，它能显著减缓ASIC1b/3异源体的脱敏，其表观解离常数约为24微摩尔。在低细胞外钙浓度下，对RFamide诱导效应的表观亲和力约高3倍。我们的结果表明，ASIC1b/3异源体可能是外周神经系统中RFamide神经肽的一个作用靶点。
