Seredenina Tamara, Demaurex Nicolas, Krause Karl-Heinz
1 Department of Pathology and Immunology, Geneva University Medical Faculty , Centre Médical Universitaire, Geneva, Switzerland .
2 Department of Cellular Physiology and Metabolism, Geneva University Medical Faculty , Centre Médical Universitaire, Geneva, Switzerland .
Antioxid Redox Signal. 2015 Aug 10;23(5):490-513. doi: 10.1089/ars.2013.5806. Epub 2014 Mar 17.
Voltage-gated proton channels are increasingly implicated in cellular proton homeostasis. Proton currents were originally identified in snail neurons less than 40 years ago, and subsequently shown to play an important auxiliary role in the functioning of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Molecular identification of voltage-gated proton channels was achieved less than 10 years ago. Interestingly, so far, only one gene coding for voltage-gated proton channels has been identified, namely hydrogen voltage-gated channel 1 (HVCN1), which codes for the HV1 proton channel protein. Over the last years, the first picture of putative physiological functions of HV1 has been emerging.
The best-studied role remains charge and pH compensation during the respiratory burst of the phagocyte NADPH oxidase (NOX). Strong evidence for a role of HV1 is also emerging in sperm biology, but the relationship with the sperm NOX5 remains unclear. Probably in many instances, HV1 functions independently of NOX: for example in snail neurons, basophils, osteoclasts, and cancer cells.
Generally, ion channels are good drug targets; however, this feature has so far not been exploited for HV1, and hitherto no inhibitors compatible with clinical use exist. However, there are emerging indications for HV1 inhibitors, ranging from diseases with a strong activation of the phagocyte NOX (e.g., stroke) to infertility, osteoporosis, and cancer.
Clinically useful HV1-active drugs should be developed and might become interesting drugs of the future.
电压门控质子通道在细胞质子稳态中的作用日益受到关注。质子电流最初是在不到40年前于蜗牛神经元中发现的，随后被证明在产生活性氧（ROS）的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的功能中起重要辅助作用。电压门控质子通道的分子鉴定是在不到10年前完成的。有趣的是，到目前为止，仅鉴定出一个编码电压门控质子通道的基因，即氢电压门控通道1（HVCN1），它编码HV1质子通道蛋白。在过去几年中，HV1假定生理功能的首张图谱逐渐浮现。
研究最充分的作用仍然是在吞噬细胞NADPH氧化酶（NOX）呼吸爆发期间的电荷和pH补偿。HV1在精子生物学中的作用也有强有力的证据出现，但与精子NOX5的关系仍不清楚。在许多情况下，HV1可能独立于NOX发挥作用：例如在蜗牛神经元、嗜碱性粒细胞、破骨细胞和癌细胞中。
一般来说，离子通道是很好的药物靶点；然而，这一特性迄今尚未用于HV1，目前也不存在与临床应用兼容的抑制剂。不过，有迹象表明HV1抑制剂可用于多种疾病，从吞噬细胞NOX强烈激活的疾病（如中风）到不孕症、骨质疏松症和癌症。
应开发临床上有用的HV1活性药物，它们可能会成为未来令人感兴趣的药物。
