Holzer Peter
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria.
Handb Exp Pharmacol. 2009(194):283-332. doi: 10.1007/978-3-540-79090-7_9.
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(+) (K(2P)) channels are differentially regulated by small deviations of extra- or intracellular pH from physiological levels. Other acid-sensitive channels include TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), ionotropic purinoceptors (P2X), inward rectifier K(+) channels, voltage-activated K(+) channels, L-type Ca(2+) 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.
酸中毒是一种与炎症、缺血或酸容纳缺陷相关的有害状态。因此，酸感应已演变为传入神经元的一项重要特性，这些传入神经元具有无髓鞘和薄髓鞘神经纤维。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）离子通道得到了最深入的研究。ASICs监测细胞外pH值的适度下降，而TRPV1仅在严重酸中毒导致pH值低于6时才被激活。双孔结构域钾离子（K(2P)）通道受细胞外或细胞内pH值与生理水平的微小偏差的差异调节。其他酸敏感通道包括TRPV4、TRPC4、TRPC5、多囊蛋白2（PKD2L1）、离子型嘌呤受体（P2X）、内向整流钾离子通道、电压激活钾离子通道、L型钙离子通道、超极化激活环核苷酸门控通道、缝隙连接通道和氯离子通道。此外，还鉴定出了酸敏感G蛋白偶联受体。尽管程度不同且组合各异，但这些分子酸传感器大多由初级感觉神经元表达。新出现的证据表明，许多酸敏感离子通道和受体在酸感应、酸诱导疼痛以及酸引发的稳态反应反馈调节中发挥作用。多种pH监测系统的存在及其明显的冗余性证明了酸碱调节对于细胞和组织稳态至关重要这一概念。由于酸传感器的上调和过度激活似乎促成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。只有当酸传感器的病理影响能够在药理学上与它们的生理功能区分开来时，这种方法才会成功。
