Acid-sensitive ion channels and receptors.
Acid-sensitive ion channels and receptors.
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DOI：
10.1007/978-3-540-79090-7_9
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发表时间：
2009
影响因子：
--
通讯作者：
Holzer, Peter
中科院分区：
文献类型：
--
作者：
Holzer, Peter
酸中毒是一种与炎症、缺血或酸性物质 containment（此处可能是“容纳、控制”方面有问题，比如酸碱平衡调节机制中对酸的控制出现缺陷，可结合更多背景知识确定准确意思）相关的有害状况。因此，酸感应已演变成具有无髓鞘和薄髓鞘神经纤维的传入神经元的一项重要特性。质子在初级传入神经元中引发多种电流，这些电流由几种酸敏感离子通道传导。其中，酸敏感离子通道（ASICs）和瞬时受体电位（TRP）香草酸受体1（TRPV1）离子通道已得到最为深入的研究。ASICs可检测细胞外pH的适度降低，而TRPV1只有在导致pH值低于6的严重酸中毒时才会被激活。双孔结构域K⁺（K2P）通道会因细胞外或细胞内pH偏离生理水平的微小变化而受到不同的调节。其他酸敏感通道包括TRPV4、TRPC4、TRPC5、TRPP2（PKD2L1）、离子型嘌呤受体（P2X）、内向整流K⁺通道、电压激活K⁺通道、L型Ca²⁺通道、超极化激活的环核苷酸门控通道、缝隙连接通道和Cl⁻通道。此外，还发现了酸敏感的G蛋白偶联受体。这些分子酸传感器大多由初级感觉神经元表达，尽管程度不同且组合各异。新出现的证据表明，许多酸敏感离子通道和受体在酸感应、酸诱导的疼痛以及酸引发的内稳态反应的反馈调节中发挥作用。多种pH监测系统的存在以及明显的冗余性证明了酸碱调节对细胞和组织内稳态是一个至关重要的问题这一概念。由于酸传感器的上调和过度活跃似乎导致了各种形式的慢性疼痛，酸敏感离子通道和受体被视为新型镇痛药的靶点。只有当能够从药理学上区分酸传感器的病理影响与其生理功能时，这种方法才会成功。
Acidosis is a noxious condition associated with inflammation, ischaemia or defective acid containment. As a consequence, acid sensing has evolved as an important property of afferent neurons with unmyelinated and thinly myelinated nerve fibres. Protons evoke multiple currents in primary afferent neurons, which are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential (TRP) vanilloid-1 (TRPV1) ion channels have been most thoroughly studied. ASICs survey moderate decreases in extracellular pH whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6. Two-pore domain K+ (K2P) channels are differentially regulated by small deviations of extra- or intracellular pH from physiological levels. Other acid-sensitive channels comprise TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), ionotropic purinoceptors (P2X), inward rectifier K+ channels, voltage-activated K+ channels, L-type Ca2+ channels, hyperpolarization-activated cyclic nucleotide-gated channels, gap junction channels, and Cl− channels. In addition, acid-sensitive G protein-coupled receptors have also been identified. Most of these molecular acid sensors are expressed by primary sensory neurons, although to different degrees and in various combinations. Emerging evidence indicates that many of the acid-sensitive ion channels and receptors play a role in acid sensing, acid-induced pain and acid-evoked feedback regulation of homeostatic reactions. The existence and apparent redundancy of multiple pH surveillance systems attests to the concept that acid-base regulation is a vital issue for cell and tissue homeostasis. Since upregulation and overactivity of acid sensors appear to contribute to various forms of chronic pain, acid-sensitive ion channels and receptors are considered as targets for novel analgesic drugs. This approach will only be successful if the pathological implications of acid sensors can be differentiated pharmacologically from their physiological function.