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。     

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。     

酸敏感离子通道在缺血性脑损伤中的作用

综述近年来有关酸敏感离子通道在缺血性脑损伤中的作用研究,论及酸敏感离子通道在脑中的分布和作用、它的激活以及在缺血性脑损伤中的作用机制及与谷氨酸受体的协同作用.酸敏感离子通道是一类由胞外酸化所激活的阳离子通道,而缺血性脑损伤正是由其引起胞内Ca^2＋超载所致,因此抑制其激活可以对抗缺血性脑损伤,为神经系统缺血性损伤的保护及药物治疗研究提供了新思路.     

酸敏感离子通道1a在自身免疫性疾病发病机制中的研究进展

酸敏感离子通道(acid-sensing ion channels,ASICs)是在外周和中枢神经系统中广泛表达的质子门控的阳离子通道,ASIC1a作为其重要的组成部分在许多生理和病理过程中起重要作用。作为细胞外质子的关键受体,ASIC1a参与涉及组织酸中毒的多种病理生理过程,如疼痛、炎症、癫痫发作、多发性硬化等。自身免疫疾病是机体在应对自身抗原发生免疫反应时,过度活化的T、B细胞导致机体多组织器官受损的慢性炎症性疾病。近年来研究发现,ASIC1a在多种自身免疫性疾病发生中发挥着重要作用,该文就ASIC1a的生物学特征作简要综述,重点探讨ASIC1a在自身免疫性疾病发病机制中的研究进展。     

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1a在酸诱导的大鼠肝星状细胞活化中的作用

目的：探讨酸敏感离子通道1a（ASIC1a）在酸诱导的大鼠肝星状细胞活化中的作用。方法：体外培养肝星状细胞株（HSC-T6）经处理后,乳酸脱氢酶（LDH）检测细胞毒性变化,RT—PCR检测ASIC1a mRNA表达,Western Blot和RT—PCR分别检测Calpain、Calcineurin蛋白和mRNA表达变化,免疫细胞化学法检测α-平滑肌肌动蛋白（α—SMA）的变化。结果：细胞酸化处理后ASIC1a含量明显上升;随着胞外pH值的下降,LDH释放量逐渐升高,ASIC1a阻滞剂可抑制酸化诱导的肝星状细胞LDH的释放量;酸化组肝星状细胞Calpain、Calcineurin mRNA和蛋白表达水平均明显增高,ASIC1a阻断剂组Calpain、Calcineurin mRNA和蛋白表达水平较酸化组明显降低;与酸化组相比,阻断ASIC1a可以降低HSC—T6中α—SMA的表达。结论：胞外酸化环境下可诱导肝星状细胞活化,阻断ASIC1a能明显降低酸化诱导的细胞活化。     

酸敏感离子通道3在关节炎疼痛中的作用

疼痛相关的酸敏感离子通道3（Acid-sensingion channels 3,ASIC3）主要分布在周围神经系统,是对pH值改变最敏感的酸受体。最近,越来越多的研究证实,在脊髓背根神经节（DRG）丰富表达的ASIC3,与痛觉及伤害性感受密切相关,在慢性炎性疼痛的病理过程中发挥重要的作用。研究表明在炎性痛模型中可以上调脊髓背角ASIC3在转录和蛋白水平的表达;阻断或敲除ASIC3基因（ASIC3-/-）能明显抑制炎症性关节痛。上述各点提示,在生理或病理情况下,脊髓背角ASIC3对脊髓水平的感觉信息传递特别是痛觉的传导可能发挥着重要作用,这可能是关节炎疼痛的治疗靶点。本文将ASIC3的生物学特征以及它在关节炎疼痛和治疗中的作用作一综述。     

酸敏感离子通道在紫癜性肾炎肾组织中的表达及其对肾损伤的影响

目的 观察酸敏感离子通道(acid-sensing ion channels,ASICs) 在紫癜性肾炎(henoch-Schnlein purpura nephritis, HSPN) 患儿肾组织中的表达并探讨其在HSPN患儿肾损伤中的作用。方法 采用免疫组化法观察HSPN患儿及单纯肾病综合征患儿肾组织中ASIC1a、ASIC2a、ASIC3 的表达部位及水平;对HSPN患儿24 h尿蛋白定量与肾组织中ASICs的表达做相关性分析,另外根据尿系列蛋白检查中的α_l-MG 和β₂-MG是否异常将HSPN患儿分为两组,观察ASICs在其两组HSPN患儿肾小管中的表达情况。 结果 免疫组化显示ASIC1a、ASIC2a 、ASIC3 在HSPN患儿肾小管上的表达较对照组显著增多(P<0.01)。ASIC3 在HSPN患儿肾小管上的表达定量与24 h尿蛋白定量呈正相关(r=0.644,P=0.017),根据尿系列蛋白检查α_l-MG 和β₂-MG是否异常将HSPN患儿分为两组,ASIC3 在α_l-MG异常组和β₂-MG异常组中的表达较对照组(正常组)显著增多(P<0.01),ASIC2a在α_l-MG异常组中的表达较对照组(正常组)增多( P<0.05)。结论 ASICs 可能参与了紫癜性肾炎肾小管的损伤过程。ASICs 与HSPN患儿蛋白尿,尤其是微量蛋白尿的产生可能存在一定关系。     

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。     

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。     

Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels

BACKGROUND AND PURPOSE

Sinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen-glucose deprivation-reperfusion (OGD-R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism.

EXPERIMENTAL APPROACH

Middle cerebral artery occlusion in rats was used as an animal model of ischaemic stroke in vivo. The mechanisms of the effects of SN were investigated in vitro using whole-cell patch-clamp recording, calcium imaging in PC12 cells and rat cortical neurons subjected to OGD-R.

KEY RESULTS

Pretreatment with SN (10 and 30 mg·kg⁻¹, i.p.) significantly decreased brain infarction and the overactivation of calcium-mediated events in rats subjected to 2 h ischaemia followed by 24 h reperfusion. Extracellular application of SN inhibited the currents mediated by acid-sensing ion channel 1a and L-type voltage-gated calcium channels, in the rat cultured neurons, in a concentration-dependent manner. These inhibitory effects contribute to the neuroprotection of SN against OGD-R and extracellular acidosis-induced cytotoxicity. More importantly, administration of SN (30 mg·kg⁻¹, i.p.) at 1 and 2 h after cerebral ischaemia also decreased brain infarction and improved functional recovery.

CONCLUSION AND IMPLICATIONS

SN exerts potent protective effects against ischaemic brain injury when administered before ischaemia or even after the injury. The inhibitory effects of SN on acid-sensing ion channel 1a and L-type calcium channels are involved in this neuroprotection.     

Current perspectives on acid-sensing ion channels: new advances and therapeutic implications

Acid-sensing ion channels (ASICs) form a family of voltage-independent cation channels that predominantly conduct Na⁺ ions, and were identified at the molecular level a little more than a decade ago. ASICs are activated by extracellular acidification within the physiological range, and they form effective proton sensors in both central and peripheral sensory neurons. A combination of genetic and pharmacologic approaches has revealed their implication in an increasing number of physiological and pathophysiological processes – most of them associated with extracellular pH fluctuations, ranging from synaptic plasticity, learning, memory, fear, depression, seizure termination and neuronal degeneration to nociception and mechanosensation. ASICs, therefore, emerge as new potential therapeutic targets in the management of psychiatric disorders, stroke, neurodegenerative diseases and pain.     

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.     

大鼠背根神经节酸感受离子通道(ASICs)的药理学特性研究

目的研究大鼠背根神经节(DRG)细胞酸感受离子通道(ASICs)的电生理学和药理学特性。方法应用全细胞膜片钳技术,在急性分散的成年大鼠DRG细胞上记录并分析由不同浓度H+(降低pH值)诱发的ASICs电流。结果在266个大鼠DRG神经元上记录到由H+诱发的3种不同类型的ASICs电流,分别为ASIC1样电流(n=66,24·8%)、ASIC2样电流(n=81,30·4%)和ASIC3样电流(n=119,44·7%)。ASIC1样电流具有快速失活成份,衰减快;ASIC2样电流具有稳态失活成份,衰减十分缓慢;而ASIC3样电流具有快速失活与稳态失活双相成份。三者均不具有整流现象。此3种电流对细胞外H+表现出不同的敏感性,H+诱发电流的pH50分别是:ASIC1-like,pH5·82;ASIC2-like,pH5·18;ASIC3-like,pH6·24。氨氯吡咪以浓度依赖性方式可逆性阻断大鼠DRG神经元的ASICs,对3种ASICs电流的抑制效应差异有显著性。其IC50分别为:ASIC1-like,19·86μmol·L-1;ASIC2-like,42·73μmol·L-1;ASIC3-like,27·91μmol·L-1。结论成年大鼠DRG神经元细胞上表达了3种不同类型的ASICs,且其在表达率、H+敏感性、失敏以及氨氯吡咪敏感性等方面差异均有显著性。     

Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction

Loss of energy supply to neurons during stroke induces a rapid loss of membrane potential that is called the anoxic depolarization. Anoxic depolarizations result in tremendous physiological stress on the neurons because of the dysregulation of ionic fluxes and the loss of ATP to drive ion pumps that maintain electrochemical gradients. In this review, we present an overview of some of the ionotropic receptors and ion channels that are thought to contribute to the anoxic depolarization of neurons and subsequently, to cell death. The ionotropic receptors for glutamate and ATP that function as ligand-gated cation channels are critical in the death and dysfunction of neurons. Interestingly, two of these receptors (P2X7 and NMDAR) have been shown to couple to the pannexin-1 (Panx1) ion channel. We also discuss the important roles of transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) in responses to ischemia. The central challenge that emerges from our current understanding of the anoxic depolarization is the need to elucidate the mechanistic and temporal interrelations of these ion channels to fully appreciate their impact on neurons during stroke.