酸敏感离子通道的研究进展

酸敏感离子通道ASICs是一类由细胞外Ph降低所激活的阳离子通道,其可在胞外酸化时激活并产生相应电位。目前研究发现,酸敏感离子通道ASICs在心血管,骨组织和膀胱内均有一定的生理或病理作用。现就ASICs对人体各组织的研究进展做一简要综述,以增进对ASICs的生理学功能和病理作用的了解。     

酸感受离子通道亚基1a的研究进展

酸感受离子通道是一类由细胞外酸化所激活的阳离子通道,在胞外H+浓度增高时离子通道开放,形成H+门控电流。目前,已发现7个ASICs亚基,ASIC1a是其中之一。研究表明,ASIC1a在突触传递及其可塑性的调节、空间学习记忆、痛觉传导和缺血性脑损伤等生理和病理过程中起重要作用。该文对有关ASIC1a研究的最新进展作一综述,以增进对ASICs生物学功能和病理作用的了解。     

ASICs——治疗神经系统相关疾病药物作用的新靶点

酸敏感离子通道（Acid sensing ion channels，ASICs）是一种可以被H+激活的质子门控阳离子通道。近年来研究发现，ASICs参与癫痫、炎症性疼痛、缺血性脑损伤等神经系统相关疾病的病理过程，它被认为是治疗神经系统相关疾病药物作用的一个新靶点。本文主要综述ASICs在神经系统相关疾病中的调节作用，以及ASICs相关药物的最新研究进展。     

酸敏感离子通道抑制剂的研究进展

酸敏感离子通道(ASICs)是一类由胞外H 激活的阳离子通道。已发现的6个ASICs亚基在触觉、痛觉、酸味觉以及学习记忆中有重要的生理作用,同时,它们参与某些病理反应,可以被神经肽、温度、金属离子以及缺血诱导产生的一些活性物质所调控。基于其病理作用,ASICs抑制剂的研发成为药物化学研究的热点之一。本文综述了近年来对ASICs的结构、生理和病理作用及几类ASICs抑制剂的最新研究进展,并进行了展望。     

酸敏感离子通道的研究进展

酸敏感离子通道(ASICs)属于DEG/ENaC家族中的一员,广泛分布于外周神经系统、中枢神经系统、消化系统等器官及某些肿瘤组织中。ASICs可以被金属离子、FMRF肽及FMRF相关肽、氧化还原剂等多种物质所调控,在包括缺血性脑损伤、轻触觉、酸味觉、痛觉、学习与记忆等多种生理及病理过程中发挥功能。     

缺血性脑损伤与瞬时受体电位M通道的研究进展

缺血性脑血管病是临床常见病、多发病,其发病机制复杂。钙超载在缺血性脑损伤中起重要作用。瞬时受体电位M通道(transient receptor potential melastatin,TRPM)是位于细胞膜上的一类重要的非选择性阳离子通道超家族,对钙离子有较高的通透性,在缺血性脑损伤中起重要作用,对TRPM通道的研究将成为治疗缺血性脑损伤新的靶点。本文就胞内钙离子超载在缺血性脑损伤中的作用、TRPM通道及其参与的缺血性脑损伤的机制予以综述。     

酸敏感离子通道与炎性痛中枢敏化机制的研究

目的：研究探讨酸敏感离子通道与炎性痛中枢敏化机制。方法对急性分离的脊髓背角神经元,经电生理研究初步判定酸敏感离子通道在炎性痛中的作用及作用机制,进行行为学实验、福尔马林实验等一系列实验,进一步确定酸敏感离子通道及炎性痛中枢敏化机制。结果钙离子通透性的ASICIa同聚体通道是脊髓背角主要存在的酸敏感离子通道;脊髓背角神经元中ASICIa的表达数目会在外周炎的条件下增多,使得脊髓背角神经元兴奋性及可塑性增强,且ASICIa通道参与炎性痛觉敏化的过程中。结论酸敏感离子通道与炎性痛中枢敏化机制是一种生物体内痛觉引发并维持的一种机制, ASICIa通道可以作为止痛类药物的靶点。     

酸敏感离子通道在类风湿关节炎中作用的研究进展

酸敏感离子通道(acid-sensing ion channels,ASICs)是一类胞外H+激活的阳离子通道,属于阿米洛利敏感的上皮钠通道/退变素(epithelial Na+channels/degenerin,ENa C/DEG)超家族中的一员,该通道广泛分布在周围和中枢神经系统中,并且具有重要的生物学功能。近来研究表明,ASICs在类风湿关节炎发病过程中发挥着重要作用。该文对ASICs的细胞生物学特点以及ASICs在类风湿关节炎中对炎症、疼痛和软骨损伤等方面的作用进行综述。     

酸感受离子通道亚基3的研究进展

酸感受离子通道(ASIC)是对H 敏感的Na 选择性阳离子通道,在细胞外H 浓度增高时激活开放,形成H 门控电流。目前,已发现该通道有6个亚基,酸感受离子通道亚基3(ASIC3)是其中之一。研究表明,ASIC3在痛觉、伤害性刺激的感受、心肌缺血所致的心绞痛等病理过程中有重要作用,很可能成为药物研制的新靶标。     

星形胶质细胞与缺血性脑损伤

星形胶质细胞是脑中存在最多的细胞类型,能够为神经元提供代谢、营养支持及调节突触活性.脑缺血等病理状态下,反应性星形胶质细胞通过一系列生化过程的改变,诸如调节能量代谢、清除兴奋性氨基酸、抗氧化作用、分泌神经保护物质等发挥神经保护作用.缺血时星形胶质细胞内相关信号通路被激活,对细胞凋亡起调控作用.星形胶质细胞中相关酶、离子通道以及信号分子都可成为潜在的治疗靶点,通过药物干预,间接发挥神经保护作用.进一步阐明星形胶质细胞在缺血性脑损伤中的作用,可以为基于星形胶质细胞的新药研发提供思路.     

酸敏感离子通道的研究进展

酸敏感通道广泛表达于中枢与外周神经系统,在疼痛、伤害感觉中发挥了重要的作用。其分子结构与分布特点、调控机制以及在某些病理生理过程中的作用已经得到了部分阐明。未来对其研究将是离子通道研究领域的热门课题。     

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

A significant drop of tissue pH or acidosis is a common feature of acute neurological conditions such as ischemic stroke, brain trauma, and epileptic seizures. Acid-sensing ion channels, or ASICs, are proton-gated cation channels widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. Recent studies have demonstrated that activation of these channels by protons plays an important role in a variety of physiological and pathological processes such as nociception, mechanosensation, synaptic plasticity, and acidosis-mediated neuronal injury. This review provides an overview of the recent advance in electrophysiological, pharmacological characterization of ASICs, and their role in neurological diseases. Therapeutic potential of current available ASIC inhibitors is discussed.     

Physiological and pathological functions of acid-sensing ion channels in the central nervous system

Protons are important signals for neuronal function. In the central nervous system (CNS), proton concentrations change locally when synaptic vesicles release their acidic contents into the synaptic cleft, and globally in ischemia, seizures, traumatic brain injury, and other neurological disorders due to lactic acid accumulation. The finding that protons gate a distinct family of ion channels, the acid-sensing ion channels (ASICs), has shed new light on the mechanism of acid signaling and acidosis-associated neuronal injury. Accumulating evidence has suggested that ASICs play important roles in physiological processes such as synaptic plasticity, learning/memory, fear conditioning, and retinal integrity, and in pathological conditions such as brain ischemia, multiple sclerosis, epileptic seizures, and malignant glioma. Thus, targeting these channels may lead to novel therapeutic interventions for neurological disorders. The goal of this review is to provide an update on recent advances in our understanding of the functions of ASICs in the CNS.     

The pharmacology and therapeutic potential of small molecule inhibitors of acid-sensing ion channels in stroke intervention

In the nervous system, a decrease in extracellular pH is a common feature of various physiological and pathological processes, including synaptic transmission, cerebral ischemia, epilepsy, brain trauma, and tissue inflammation. Acid-sensing ion channels (ASICs) are proton-gated cation channels that are distributed throughout the central and peripheral nervous systems. Following the recent identification of ASICs as critical acid-sensing extracellular proton receptors, growing evidence has suggested that the activation of ASICs plays important roles in physiological processes such as nociception, mechanosensation, synaptic plasticity, learning and memory. However, the over-activation of ASICs is also linked to adverse outcomes for certain pathological processes, such as brain ischemia and multiple sclerosis. Based on the well-demonstrated role of ASIC1a activation in acidosis-mediated brain injury, small molecule inhibitors of ASIC1a may represent novel therapeutic agents for the treatment of neurological disorders, such as stroke.     

Dynamic regulation of acid-sensing ion channels by extracellular and intracellular modulators

Changes of extracellular pH values can have profound effects on neuronal function. For example, the low pH (also called acidosis) generated in brain ischemia causes acute neuronal injury. For years the receptors that detect pH variations surrounding neurons and their physiological/pathological importance remain uncertain. The recent finding that acidosis activates a distinct family of membrane ion channels, the acid-sensing ion channels (ASICs) in both peripheral and central neurons has dramatically changed the view of acidosis-associated signaling and provided a new strategy for therapeutic inventions. Although proton is the only known agonist for the activation of ASICs, a variety of extracellular and intracellular signaling molecules can modulate the activities of ASICs and have profound influence on the functions of these channels in both physiological and pathological processes. The goal of this article is therefore to provide a comprehensive review of the modulators of ASICs that adapt ASIC activity to changes of extracellular and intracellular environments.     

omega-agatoxin IVA-sensitive Ca(2+) channel blocker, alpha-eudesmol, protects against brain injury after focal ischemia in rats

omega-Agatoxin IVA-sensitive Ca(2+) channels have been thought to be involved in physiological excitatory amino acid glutamate release and these channels may also contribute to the development of ischemic brain injury. Recently, we demonstrated that alpha-eudesmol from Juniperus virginiana Linn. (Cupressaceae) inhibits potently the presynaptic omega-agatoxin IVA-sensitive Ca(2+) channels. In the present study, we investigated the effects of alpha-eudesmol on brain edema formation and infarct size determined after 24 h of reperfusion following 1 h of middle cerebral artery occlusion in rats. We first found that alpha-eudesmol concentration-dependently inhibited glutamate release from rat brain synaptosomes and that its inhibitory effect was Ca(2+)-dependent. In the middle cerebral artery occlusion study, intracerebroventricular (i.c.v.) treatment with alpha-eudesmol significantly attenuated the post-ischemic increase in brain water content. alpha-Eudesmol also significantly reduced the size of the infarct area determined by triphenyltetrazolium chloride staining after 24 h of reperfusion. Using a microdialysis technique, we further demonstrated that alpha-eudesmol inhibits the elevation of the extracellular concentration of glutamate during ischemia. From these results, we suggest that alpha-eudesmol displays an ability to inhibit exocytotic glutamate release and to attenuate post-ischemic brain injury.     

Diarylamidines: High potency inhibitors of acid-sensing ion channels

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are predominantly expressed in the nervous system. ASICs are involved in a number of neurological diseases such as pain, ischemic stroke and multiple sclerosis but limited tools are available to target these channels and provide probes for their physiological functions. Here we report that the anti-protozoal diarylamidines, 4′,6-diamidino-2-phenylindole (DAPI), diminazene, hydroxystilbamidine (HSB) and pentamidine potently inhibit ASIC currents in primary cultured hippocampal neurons with apparent affinities of 2.8 μM, 0.3 μM, 1.5 μM and 38 μM, respectively. These four compounds (100 μM) failed to block ENaC channels expressed in oocytes. Sub-maximal concentrations of diminazene also strongly accelerated desensitization of ASIC currents in hippocampal neurons. Diminazene blocked ASIC1a, -1b -2a, and -3 currents expressed in CHO cells with a rank order of potency 1b > 3 > 2a ≥ 1a. Patchdock computational analysis suggested a binding site of diarylamidines on ASICs. This study indicates diarylamidines constitute a novel class of non-amiloride ASIC blockers and suggests that diarylamidines may be developed as therapeutic agents in treatment of ASIC-involved diseases.     

Tetraethylammonium exacerbates ischemic neuronal injury in rat cerebrocortical slice cultures

We investigated potential contribution of K+ channel activity to regulation of ischemia-induced neuronal injury, using cerebrocortical slice cultures. Exposure of cultures to a glucose-free conditioning solution containing sodium azide and 2-deoxyglucose caused neuronal cell death as assessed by cellular uptake of propidium iodide, which was prevented by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist. Application of tetraethylammonium markedly exacerbated ischemic neuronal injury. Charybdotoxin, a blocker of large-conductance Ca(2+)-activated K+ (BK(Ca)) channels, also augmented ischemic injury, whereas AM 92016, a blocker of delayed rectifier K+ channels, and dequalinium, a blocker of small-conductance Ca(2+)-activated K+ channels, had no significant effect. In addition, tetraethylammonium and charybdotoxin were effective in augmenting NMDA-induced neuronal injury. These results present unprecedented evidence for the ability of tetraethylammonium to enhance ischemic neuronal death, and suggest that BK(Ca) channels constitute an endogenous system to protect cortical neurons from ischemic injury, via prevention of NMDA receptor over-activation.