离子通道和自闭分享分享

Name : Date: 12.24,Wei-Qun Fang, Wei-Wei Chen,2014,Autismis a severe neuro devel opmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication and repetitive behavior and restricted interests.,Introduction,Inwardly-rectifying potassium channel 4.1(Kir4.1),Kir4.1 channels oligodendrocytes astrocytescortex thalamus hippocampus brainstemthe resting membrane potential of astrocytes maintain the extracellular ionic and osmoticneuronal activity excitability synaptic functions.,Paula A. Garay and A. Kimberley McAllister* ，2010,Materials,Mutation analyses of KCNJ10 and KCNJ16 were performed in 52 patients.,Molecular genetic analyses(分子遗传分析),Electrophysiology（电生理）,Homology modeling（同源建模）,methods,In this study, they have investigated the frequency of KCNJ10 and KCNJ16 variants in a cohort of patients in whom epilepsy of“unknown cause” was associated with impairment of either cognitive or communicative abilities or both.,Three children display seizures, Autism Spectrum Disorders (ASD) and intellectual disability.,Results,5 years old,persistent motor delay, clumsiness, produced his rst words.,At 5 months, impaired social interaction,sleep difculties and hypotonia were apparent for both twins. At the age of 7 months, within 24 h, both exhibited epileptic spasms that remitted under ACTH.,At 10 months, Patient A-III:2 was seizure-free,whereas his twin brother had persisting seizures that stopped at 12 months on valproate-topiramate bitherapy.,18 months :ASD6 years old: Autistic features,severe decit in social and communicative skills, stereotyped and repetitive behaviors, severe mental retardation, and self- andother-directed injurious behaviors.,Mutation detection by sequencing. Electropherograms of exon 2 anking the mutations in KCNJ10 in unaffected individuals (WT) and propositi in affected kindred (A-III:1, B-III:1). The positions of the heterozygous mutations are arrow-headed and the predicted effect of the mutation is shown below. Patient A-III:1 displayed a heterozygous c.53GNA transition, predicting a novel non-synonymous p.R18Q variant. This mutation was also identied in patient A-III:2. Patient B-III:1 harbored a heterozygous c.250GNA transition predicting a novel p.V84M.,Arg-Gln,Val-Met,Transmembrane domains (TM),3D-homology model of a heteromeric Kir4.1/Kir5.1 channel indicating the position of Val-84.,Close-up view of the channel indicating the position of Val-84 in the rst transmembrane domain that has been changed into methionine,These results indicate that the R18Q and V84M mutations enhance heteromeric current amplitudes and result in inwardly-rectifying K+ currents with faster activation kinetics than the wild-type.,They exhibit smaller instantaneous current, a timedependent “relaxation” at hyperpolarized potentials, and a dramatic increase in sensitivity to inhibition by intracellular H+ (pHi) . Both mutations increased the instantaneous current and nearly nullied the slow “relaxation”component of Kir4.1/Kir5.1 channels. Conversely, their pHi sensitivity was not changed.,Discussion,Epilepsy and ASD are strongly associated. The prevalence ofseizures is over represented in ASD (546%), compared with the general population(0.51%). The prevalence of autism in the epilepsy population is approximately 32%,which is about 50 times higher than in the general population .An “autismepilepsy phenotype”has been identied and shared pathogenetic mechanisms have been hypothesized.,the p.V84M mutation that is located in TM1, near the membrane/ water interface, mainly increased the single-channel conductance producing a gain-of-function effect.,Both p.R18Q and p.V84M caused a dramatic increase in the instantaneous current of heteromeric Kir4.1/Kir5.1 channels and nearly abolished the slow component of the current, denoting a more efcient and faster response of the mutated channels.,The relationship between KCNJ10 and ASD seems less straight forward.However, a recent linkage analysis study on a large Finnish pedigree has proposed KCNJ10 as a candidate gene for ASD .,Thank you,Kir4.1 channels are expressed primarily in oligodendrocytes and in astrocytes surrounding synapses and blood vessels, mainly in the cortex, thalamus, hippocampus, and brainstem. They control the resting membrane potential of astrocytes and are believed to maintain the extracellular ionic and osmotic environment by promoting K+ transport from regions of high K+ o, which results from synaptic excitation, to those of low K+ o. This polarized transport of K+ in astrocytes, referred to as “spatial buffering of K+ ,” is essential for normal neuronal activity, excitability,and synaptic functions.,Expresse and control,Kir5.1 subunits assemble selectively with Kir4.1,conferring several unique properties to heteromeric Kir4.1/Kir5.1 channels as compared to homomeric Kir4.1, but most importantly they exhibit smaller instantaneous current, a timedependent“relaxation” at hyperpolarized potentials, and a dramatic increase in sensitivity to inhibition by intracellular H+ (pHi) .Thus, we characterized the effects of both variants also on the biophysical properties and pHi sensitivity of heteromeric Kir4.1/Kir5.1 channels. Both mutations increased the instantaneous current and nearly nullied the slow “relaxation”component of Kir4.1/Kir5.1 channels. Conversely, their pHi sensitivity was not changed.,Khakh和Sofroniew检测了亨廷顿突变如何影响大脑中的星形胶质细胞。特别是，他们研究了星形胶质细胞与一种类型的神经元之间的相互作用，这种神经元在协调运动过程中发挥重要的作用。一个关键的发现从数据中脱颖而出。在这两种模型中，具有突变基因的星形胶质细胞表现出Kir4.1（使星形胶质细胞通过细胞膜吸收钾的一个蛋白）的显著下降。这在细胞外留下了太多的钾，破坏了化学平衡，增加了附近神经元的兴奋性或放电的能力。Sofroniew称：“我们怀疑，基因突变，通过减少星形胶质细胞中的Kir4.1水平，引起了亨廷顿氏病。反过来，这也会降低细胞的钾吸收能力。”他补充说：“当过量的钾集中在神经元周围时，神经元就变得过分敏感，太容易放电，破坏神经细胞功能，最终破坏身体正常行动的能力。这可能导致了亨廷顿氏病常见的不平稳行动。”为了检验他们的假设，科学家们探索了“如果他们人为地增加星形胶质细胞内的Kir4.1水平会发生什么？”在一个实例中，结果非常的惊人。Khakh称：“提高星形胶质细胞内的Kir4.1水平，可改善小鼠的正常行走能力。我们惊讶地看到，小鼠的步幅长度和宽度都回归到正常水平。这是一个意想不到的发现。”,根据加州大学洛杉矶分校（UCLA）在2014年3月30日的自然神经科学（Nature Neuroscience）发表的一项研究报道，调整一个特定细胞类型在大脑中的钾吸收能力，可改善亨廷顿氏病小鼠模型的行走能力，并延长其存活时间。这一发现可为这种毁灭性疾病指出新的药物靶点。,Autismis a severe neuro developmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication and repetitive behavior and restricted interests.,Autistic spectrum disorders (ASD) are complex, pervasive developmental disorders of childhood characterized by impairments in social interaction, deficits in verbal and non-verbal communication and restricted repetitive and stereotyped patterns of behavior and interests.,Introduction,These results indicate that the R18Q and V84M mutations enhance heteromeric current amplitudes and result in inwardly-rectifying K+ currents