老化对视觉注意调控网络的影响

目的 老龄化是日益严重的社会性问题。老年人的认知功能，如注意等，出现了明显的衰退。探究老化过程中视觉注意调控网络的改变有助于理解老年人认知功能衰退的神经机制，并为寻找潜在的干预方式提供理论基础。方法 本研究采用经典的双目标注意任务：被试仅需全程注视屏幕中心的黑十字。黑十字左右两侧13.5°视角度会呈现两个相同的视觉圆点，800~1 200 ms后其中随机一个目标会发生改变或者不变。通过采集该视觉注意任务期间的脑电活动信号，比较青年人与老年人在视觉目标改变和不变两种条件下的大脑活动。结果 实验发现在青年人中，额叶、顶叶和颞叶等脑区的电极记录到的神经电活动特征对视觉目标是否改变存在显著性差别，而老年人的脑活动对该视觉目标改变无显著性变化。此外，还发现该脑网络的变化在青年人和老年人中均存在性别差异。结论 注意任务下老年人脑网络难以对外界视觉信息输入做出及时响应，老化过程伴随视觉注意调控网络（额叶、顶叶和颞叶等）功能的衰退，该脑网络的变化存在性别差异。本研究为老化引起视觉注意调控网络损伤提供了新的证据。     

13例SCN2A 基因突变相关儿童神经系统疾病表型分析

摘要 目的：总结并分析SCN2A基因突变引起的儿童神经系统疾病相关表型谱特点。方法：采用回顾性研究,收集2018年6月至2021年6月在上海交通大学医学院附属上海儿童医学中心神经内科诊治的患儿,并经二代基因测序检测,纳入SCN2A基因突变者,研究并总结患儿神经系统临床表型特点。结果：共纳入13例SCN2A突变患儿,包括新生突变9例和遗传性突变4例。其中11例患儿伴有癫痫发作,发作年龄为1日龄~1岁11月龄,4例在新生儿期起病 （36%）,1~3 月龄起病2例（18%）,4~12月龄起病2例（18%）,1岁后起病3例（27%）;发作类型中强直阵挛发作、痉挛发作、局灶性发作均各有4例（36%）,阵挛发作1例（9%）。另有2例无癫痫发作的患儿,1例表现为全面性发育迟缓,另一例表现为发育迟缓合并孤独症谱系疾病。11例癫痫患儿中,丛集性发作患儿10例。遗传性突变4例患儿中2例智力、运动发育正常;9例新生突变的患儿中8例伴有运动、智力发育落后,1例发育正常。11例癫痫患儿表型中良性家族性新生儿癫痫1例,新生儿惊厥2例,婴儿痉挛症2例,不能分类的早发性癫痫性脑病3例,儿童期起病的癫痫性脑病2例,热厥附加症1例。结论：SCN2A基因突变引起的儿童神经系统疾病以癫痫表现居多、癫痫表型谱广,少数表现为不伴癫痫发作的发育迟缓和孤独症谱系疾病。     

太赫兹刺激听神经的测试平台搭建

目的 近年来，用于脑功能调控的神经调控技术蓬勃发展，很多方法已在临床上被推广应用，主要包括电极深部脑刺激、经颅磁刺激、光遗传技术、超声深脑刺激等。但是这些调控技术存在刺激靶点改变灵活性差、空间分辨率不足、需要注射病毒转染等问题。与这些技术相比，太赫兹波调控则能以较高的时空分辨率、无需引入外源基因的方式对神经活动进行干预。激光神经刺激是一种具有较明确靶向性的刺激方法，可以通过调整不同激光参数（激光波长、脉冲能量等）控制引起神经兴奋或者抑制。但是由于该研究方向的实验手段和实验平台的缺乏，相关研究开展较少。方法 针对这个问题，从听觉神经入手，在分子、细胞和在体不同层面为相关领域的研究搭建了不同的测试平台。结果 实验结果表明，这些系统在时间和空间上具有良好的耦合性和靶向性，测得的信号受噪音干扰小。结论 这些系统可以有效测试神经系统对太赫兹刺激的响应并精确控制刺激时间和位置。     

镉胁迫对2种油菜土壤真菌群落的影响

[背景] 人类活动引起的农田重金属污染已成为严重的环境问题。镉（Cd）是最具毒性的重金属之一,能对人体和生态系统构成威胁。[目的] 研究不同浓度镉处理对2种油菜（甘蓝型油菜和芥菜型油菜）的土壤（根际和非根际）真菌群落的影响,为镉的生物修复和健康风险评估提供理论基础。[方法] 对2种油菜土壤（根际和非根际）真菌转录间隔区（Internal Transcribed Spacer,ITS）进行高通量测序,分析镉对根际和非根际土壤真菌群落的影响。[结果] 镉胁迫改变了土壤真菌群落的组成和结构,但对2种油菜土壤真菌群落的α多样性几乎无显著影响。土壤镉浓度和生物量与2种油菜根际土壤真菌群落显著相关,芥菜型油菜非根际土壤真菌群落也与镉污染浓度显著相关。土壤真菌分子生态网络也受到镉污染的影响,甘蓝型油菜根际土壤网络稳定性降低,共生关系减少。甘蓝型油菜非根际土壤网络稳定性升高,但共生关系减少。芥菜型油菜的根际和非根际土壤的网络稳定性升高,而且共生关系增多。[结论] 镉污染会影响土壤系统中的本土真菌群落,从而可能进一步改变土壤的生态系统功能。     

DTI和功能磁共振成像对精神分裂症患者脑功能连接强度的临床研究

摘要 目的：探讨DTI和功能磁共振成像对精神分裂症患者脑功能连接强度的临床研究。方法：选取2017年9月-2021年3月在我院精神科就诊的精神分裂患者96例。将纳入的96例患者作为精神分裂组,选择同时期招募的96例健康志愿者作为对照组。使用FMRIB软件库进行结构数据预处理和脑解剖网络构建,并进行相关的分析。结果：精神分裂组较对照组枕叶模块功能连接强度增强,较对照组皮质模块和额顶叶模块功能连接强度减弱（P<0.05）,精神分裂组与对照组的默认模块和中央模块功能连接强度比较无差异（P>0.05）。精神分裂组与对照组各模块的结构连接强度比较无差异（P>0.05）。精神分裂组较对照组默认模式模块和中央模块的结构-功能连接程度增加,精神分裂组较对照组枕叶模块和皮质模块的结构-功能连接程度降低（P<0.05）,额顶叶模块结构-功能连接程度两组比较无差异（P>0.05）。在精神分裂症组中,枕叶模块的结构-功能连接评分与疾病持续时间（r=-0.528,P=0.006）和PANSS总体症状相关（r=-0.174,P=0.003）,皮质模块的结构-功能连接评分也与PANSS整体症状（r=-0.405,P=0.034）显著负相关。皮质模块的结构-功能连接评分与疾病持续时间之间显著负相关（r=-0.336,P=0.029）。结论：精神分裂症患者的脑功能连接强度（功能模块水平上结构-功能耦合）发生改变,其结构-功能耦合的畸变与精神分裂症的临床特征相关。     

癫痫患者睡眠障碍特点及失眠症状与认知功能、焦虑抑郁的关系研究

摘要 目的：探讨癫痫患者的睡眠障碍特点,分析失眠症状与认知功能、焦虑抑郁的关系。方法：纳入我院2018年2月至2020年6月收治的120例癫痫患者为研究对象（癫痫组）,依据失眠严重指数量表（ISI）总分将其分为失眠组（ISI总分≥15分）与无失眠组（ISI总分＜15分）。另选取50例健康体检者为健康对照组,探讨癫痫患者睡眠障碍特点,分析失眠症状与认知功能和焦虑抑郁的关系。结果：癫痫组匹兹堡睡眠质量指数量表（PSQI）评分（4.45±1.26）分、ISI评分（12.35±5.63）分、Epworth嗜睡量表（ESS）评分（6.32±3.54）分均高于健康对照组的（3.11±1.03）分、（9.62±5.14）分、（5.12±3.06）分,差异有统计学意义（P＜0.05）。癫痫失眠者占19.17%（23/120）,无失眠者占80.83%（97/120）。失眠组病程、ISI评分、发作类型与无失眠组比较差异有统计学意义（P＜0.05）。失眠组蒙特利尔认知评估量表(MoCA)总分低于无失眠组,贝克抑郁量表第2版（BDI-Ⅱ）评分、贝克焦虑量表（BAI）评分高于无失眠组,差异有统计学意义（P＜0.05）。Pearson相关分析显示：癫痫患者ISI总分与MoCA总分呈负相关（P＜0.05）,与BDI-Ⅱ评分、BAI评分呈正相关（P＜0.05）。结论：癫痫患者多存在睡眠障碍,且认知功能、焦虑抑郁症状与失眠症状密切相关。     

海马中的内源性爆发式放电神经元与颞叶癫痫

颞叶癫痫(temporal lobe epilepsy,TLE)是常见的难治性癫痫,主要累及到海马及海马旁结构等边缘网络。爆发式放电神经元(bursting—firing neurons,BFNs)的活动是促使海马结构产生癫痫电活动及相关病理性改变的重要因素之一。BFNs是一类能够由刺激引起、甚至自发产生成串高频爆发式放电(bursting)的神经元。爆发式放电增加了突触传递的效率,促使突触活动产生短时程和长时程可塑性变化,募集邻近神经元产生同步化放电。BFNs的电活动在癫痫相关性电活动中可能具有起搏点的作用。同时,癫痫电活动也促使内源性BFNs的改变,以及调制非爆发式放电神经元向BFNs的转变,导致海马结构内癫痫电活动的进展和扩散,最终促使癫痫相关性病理性改变和脑的高级功能的损害。     

人分泌型磷脂酶A2-IIA的功能性动力学特征研究

目的 人分泌型磷脂酶A₂-IIA（secretory phospholipase A₂ group IIA,sPLA₂-IIA）在调节细胞脂质代谢和信号传导中具有重要作用,参与了多种急、慢性炎症反应。研究其动力学和变构与功能的关系具有重要意义。方法 利用弹性网络模型（elastic network model,ENM）、微扰响应扫描（perturbation-response scanning,PRS）和蛋白质结构网络（protein structure network,PSN）方法对来自人sPLA₂-IIA的31个分子的结构动力学和变构效应进行分析,并探索其动力学共性和特异性与功能的关系。结果 结果表明,对酶的催化和结构稳定起关键作用的催化残基和参与二硫键形成的半胱氨酸残基具有低运动性,这是对酶共有功能的要求;而涉及与钙离子或膜结合的5个结构区域具有高运动性,它们体现了酶成员的特异性。另外,高运动性区域在PRS分析中显示出对外界微扰响应的高敏感性,表明其在变构调节中起重要作用,而低敏感性残基则在维持结构稳定方面发挥了重要作用。残基运动相关性分析发现,人sPLA₂分子催化位点周围的强相关运动有利于酶催化功能的发挥。结论 本研究有助于深入理解人sPLA₂-IIA成员分子的动力学及功能性变构机制,可为药物设计和准确设计具有精细调节活性的蛋白质提供指导。     

儿童失神癫痫的默认模式网络的结构连接研究

大脑结构连接是其功能连接的物质基础．已有研究表明,失神癫痫患者默认模式网络(default mode network,DMN)中的功能连接发生了改变．为了探索这些改变相应的结构基础,对11名儿童失神癫痫患者和12名正常对照,使用基于弥散张量成像(diffusion tensor imaging,DTI)的纤维束追踪技术,构建了每个被试DMN脑区间的纤维束连接．结果表明,在所有被试的DMN网络中一致发现后扣带/楔前叶到内侧前额叶、后扣带/楔前叶到左右双侧的内侧颞叶都存在纤维束连接．通过两组间统计比较这些纤维束连接的平均长度、连接强度、平均部分各向异性(fractional anisotropic,FA)值和平均弥散度(mean diffusivity,MD)值等参数,发现患者组的后扣带/楔前叶到内侧前额叶纤维束连接上的平均FA值及连接强度都显著降低,而平均MD值显著增加,并且其FA值与癫痫病程呈显著的负相关关系,这些改变可能影响了患者DMN网络的功能连接．本研究结果为DMN功能连接异常提供了相关的结构上的依据,提示后扣带/楔前叶到内侧前额叶的连接异常可能在儿童失神癫痫中起着非常重要的作用．     

超声联合神经刺激仪定位腰丛－－骶丛神经阻滞对高龄股骨头置换术患者血流动力学、心理状态及认知功能的影响

摘要 目的：探讨超声联合神经刺激仪定位腰丛－－骶丛神经阻滞对高龄股骨头置换术患者血流动力学、心理状态及认知功能的影响。方法：选取2017年4月~2020年3月期间我院收治的行股骨头置换术的高龄患者98例,采用随机数字表法分为对照组和研究组,各49例,对照组给予神经刺激仪定位腰丛－－骶丛神经阻滞,研究组在此基础上联合超声引导,比较两组血流动力学、心理状态、认知功能、临床指标及不良反应。结果：两组T1~T4时间点收缩压（SBP）、心率（HR）、舒张压（DBP）组间及组内比较均未见明显差异（P>0.05）。研究组阻滞起效时间、阻滞持续时间、术后镇痛持续时间长于对照组,阻滞完成时间、术后下床活动时间短于对照组（P<0.05）。两组术后1 d回忆能力、瞬时记忆力、注意力和计算力、定向力、语言能力评分均下降,但研究组高于对照组（P<0.05）,研究组的术后认知功能障碍（POCD）发生率低于对照组（P<0.05）。两组术后1 d焦虑自评量表（SAS）和抑郁自评量表（SDS）评分均下降,且研究组低于对照组（P<0.05）。两组不良反应发生率比较无差异（P>0.05）。结论：超声联合神经刺激仪定位腰丛－骶丛神经阻滞对高龄股骨头置换术患者阻滞效果确切,对其血流动力学影响轻微,可减轻其认知功能损害,改善其负性情绪。     

Functional Brain Dysfunction in Patients with Benign Childhood Epilepsy as Revealed by Graph Theory

There is growing evidence that brain networks are altered in epileptic subjects. In this study, we investigated the functional connectivity and brain network properties of benign childhood epilepsy with centrotemporal spikes using graph theory. Benign childhood epilepsy with centrotemporal spikes is the most common form of idiopathic epilepsy in young children under the age of 16 years. High-density EEG data were recorded from patients and controls in resting state with eyes closed. Data were preprocessed and spike and spike-free segments were selected for analysis. Phase locking value was calculated for all paired combinations of channels and for five frequency bands (δ, θ, α, β₁ and β₂). We computed the degree and small-world parameters—clustering coefficient (C) and path length (L)—and compared the two patient conditions to controls. A higher degree at epileptic zones during interictal epileptic spikes (IES) was observed in all frequency bands. Both patient conditions reduced connection at the occipital and right frontal regions close to the epileptic zone in the α band. The “small-world” features (high C and short L) were deviated in patients compared to controls. A changed from an ordered network in the δ band to a more randomly organized network in the α band was observed in patients compared to healthy controls. These findings show that the benign epileptic brain network is disrupted not only at the epileptic zone, but also in other brain regions especially frontal regions.     

PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).     

托吡酯、卡马西平与丙戊酸钠治疗脑炎继发癫痫的疗效比较

目的:观察和比较托吡酯、卡马西平与丙戊酸钠对治疗脑炎继发癫痫的临床疗效及安全性。方法:选择2013年1月~2015年9月在我院进行诊治的脑炎继发癫痫患者80例,随机分为托吡酯组、卡马西平组和丙戊酸钠组,分别采用托吡酯、卡马西平与丙戊酸钠治疗,比较三组的治疗有效率、执行能力与视空间、命名、抽象、注意、定向、语言以及延迟回忆等认知功能评分及不良反应的发生情况。结果:托吡酯组的有效率最高,为80.65%(25/31),卡马西平组的有效率最低,为70.00%(21/30),但三组间有效率相比差异无统计学意义(P0.05)。治疗后,托吡酯组患者的执行能力与视空间、命名、抽象、注意、定向、语言以及延迟回忆等认知功能评分均明显高于卡马西平组和丙戊酸钠组(P0.05);托吡酯组的不良反应发生率(12.90%)明显低于卡马西平组(36.67%)和丙戊酸钠组的(29.62%)(P0.05)。结论:托吡酯、卡马西平以及丙戊酸钠治疗脑炎继发癫痫疗效相当,但托吡酯对患者认知功能损害最小,安全性最高。     

Onchocerca volvulus and epilepsy: A comprehensive review using the Bradford Hill criteria for causation

BackgroundThe possibility that onchocerciasis may cause epilepsy has been suggested for a long time, but thus far, an etiological link has not been universally accepted. The objective of this review is to critically appraise the relationship between Onchocerca volvulus and epilepsy and subsequently apply the Bradford Hill criteria to further evaluate the likelihood of a causal association.MethodsPubMed and gray literature published until September 15, 2020, were searched and findings from original research were synthesized. Adherence to the 9 Bradford Hill criteria in the context of onchocerciasis and epilepsy was determined to assess whether the criteria are met to strengthen the evidence base for a causal link between infection with O. volvulus and epilepsy, including the nodding syndrome.ResultsOnchocerciasis as a risk factor for epilepsy meets the following Bradford Hill criteria for causality: strength of the association, consistency, temporality, and biological gradient. There is weaker evidence supporting causality based on the specificity, plausibility, coherence, and analogy criteria. There is little experimental evidence. Considering the Bradford Hill criteria, available data suggest that under certain conditions (high microfilarial load, timing of infection, and perhaps genetic predisposition), onchocerciasis is likely to cause epilepsy including nodding and Nakalanga syndromes.ConclusionApplying the Bradford Hill criteria suggests consistent epidemiological evidence that O. volvulus infection is a trigger of epilepsy. However, the pathophysiological mechanisms responsible for seizure induction still need to be elucidated.     

LGI proteins in the nervous system

The development and function of the vertebrate nervous system depend on specific interactions between different cell types. Two examples of such interactions are synaptic transmission and myelination. LGI1-4 (leucine-rich glioma inactivated proteins) play important roles in these processes. They are secreted proteins consisting of an LRR (leucine-rich repeat) domain and a so-called epilepsy-associated or EPTP (epitempin) domain. Both domains are thought to function in protein–protein interactions. The first LGI gene to be identified, LGI1, was found at a chromosomal translocation breakpoint in a glioma cell line. It was subsequently found mutated in ADLTE (autosomal dominant lateral temporal (lobe) epilepsy) also referred to as ADPEAF (autosomal dominant partial epilepsy with auditory features). LGI1 protein appears to act at synapses and antibodies against LGI1 may cause the autoimmune disorder limbic encephalitis. A similar function in synaptic remodelling has been suggested for LGI2, which is mutated in canine Benign Familial Juvenile Epilepsy. LGI4 is required for proliferation of glia in the peripheral nervous system and binds to a neuronal receptor, ADAM22, to foster ensheathment and myelination of axons by Schwann cells. Thus, LGI proteins play crucial roles in nervous system development and function and their study is highly important, both to understand their biological functions and for their therapeutic potential. Here, we review our current knowledge about this important family of proteins, and the progress made towards understanding their functions.     

A multivariate population density model of the dLGN/PGN relay

Using a population density approach we study the dynamics of two interacting collections of integrate-and-fire-or-burst (IFB) neurons representing thalamocortical (TC) cells from the dorsal lateral geniculate nucleus (dLGN) and thalamic reticular (RE) cells from the perigeniculate nucleus (PGN). Each population of neurons is described by a multivariate probability density function that satisfies a conservation equation with appropriately defined probability fluxes and boundary conditions. The state variables of each neuron are the membrane potential and the inactivation gating variable of the low-threshold Ca²⁺ current I_T. The synaptic coupling of the populations and external excitatory drive are modeled by instantaneous jumps in the membrane potential of postsynaptic neurons. The population density model is validated by comparing its response to time-varying retinal input to Monte Carlo simulations of the corresponding IFB network composed of 100 to 1000 cells per population. In the absence of retinal input, the population density model exhibits rhythmic bursting similar to the 7 to 14 Hz oscillations associated with slow wave sleep that require feedback inhibition from RE to TC cells. When the TC and RE cell potassium leakage conductances are adjusted to represent cholingergic neuromodulation and arousal of the network, rhythmic bursting of the probability density model may either persists or be eliminated depending on the number of excitatory (TC to RE) or inhibitory (RE to TC) connections made by each presynaptic cell. When the probability density model is stimulated with constant retinal input (10–100 spikes/sec), a wide range of responses are observed depending on cellular parameters and network connectivity. These include asynchronous burst and tonic spikes, sleep spindle-like rhythmic bursting, and oscillations in population firing rate that are distinguishable from sleep spindles due to their amplitude, frequency, or the presence of tonic spikes. In this context of dLGN/PGN network modeling, we find the population density approach using 2,500 mesh points and resolving membrane voltage to 0.7 mV is over 30 times more efficient than 1000-cell Monte Carlo simulations. Action Editor: David Golomb     

水热增加下黑土细菌群落共生网络特征

黑土是有机质含量高且肥沃的土壤类型之一,气候变化会显著改变黑土中微生物群落的结构,同时影响群落间的潜在相互作用关系。[目的] 揭示水热增加对黑土中的细菌群落结构及潜在互作关系的影响。[方法] 基于土壤移置试验,采用16S rRNA高通量测序解析农田黑土（原位黑土、水热增加1和水热增加2）中的细菌群落结构对水热增加的响应;使用CoNet构建微生物群落共生网络,识别共生网络中的枢纽微生物;利用结构方程模型、相关性分析探究水热条件变化下土壤性质、微生物交互作用、多样性之间的直接、间接关系。[结果] 黑土中的微生物以疣微菌、变形杆菌、酸性杆菌和放线菌为主。水热增加下土壤微生物共生网络的拓扑性质发生显著变化,网络中表征微生物潜在竞争关系的负连线随着水热增加而显著增加。气候因素通过改变微生物潜在相互作用影响了群落水平分类多样性。物种竞争增强可能直接导致了土壤有机碳含量的降低。[结论] 水热增加会显著改变黑土中微生物之间的潜在交互作用,枢纽微生物的响应更加敏感。     

视频脑电图鉴别诊断癫痫患者睡眠障碍、认知障碍的临床价值研究

目的:探讨视频脑电图诊断癫痫患者睡眠障碍、认知障碍的临床价值。方法:选取2014年1月~2016年12月在我院神经内科进行诊治的癫痫患者236例作为癫痫组,另选取同期的健康患者家属或者其他健康体检者236例作为正常对照组,对两组进行视频脑电图联合睡眠参数分析;并对癫痫组视频脑电图联合认知参数进行分析。结果:癫痫组睡眠Ⅰ~Ⅱ期时间显著长于正常对照组且具有统计学差异(P=0.000),睡眠Ⅲ~Ⅳ期时间显著短于正常对照组且具有统计学差异(P=0.000),睡眠时相转换频率、觉醒指数均显著高于正常对照组且均具有统计学差异(P=0.000);清醒期、睡眠期不同痫样放电指数(IED)的WAIS-RC IQ和WMS-RC MQ均具有统计学差异(P0.05),10%IED≤50%者的WAIS-RC IQ和WMS-RC MQ均显著低于1%IED≤10%者且均具有统计学差异(P0.05),IED 10%可能是痫样放电影响患者认知功能的最低阈值。结论:视频脑电图在癫痫患者睡眠障碍、认知障碍识别中具有重要的临床价值。     

A novel degradation signal derived from distal C-terminal frameshift mutations of KCNQ2 protein which cause neonatal epilepsy

Benign familial neonatal convulsions is an autosomal-dominant idiopathic form of epilepsy primarily caused by gene mutations of the voltage-gated Kv7.2/KCNQ2/M-channel that exert only partial dominant-negative effects. However, the mechanism underlying the incomplete dominance of channel mutations, which cause epilepsy in infancy, remains unknown. Using mutagenesis and biochemistry combined with electrophysiology, we identified a novel degradation signal derived from distal C-terminal frameshift mutations, which impairs channel function. This degradation signal, transferable to non-channel CD4, can lead to accelerated degradation of mutant proteins through ubiquitin-independent proteasome machinery but does not affect mRNA quantity and protein trafficking. Functional dissection of this signal has revealed a key five-amino acid (RCXRG) motif critical for degradation. Taken together, our findings reveal a mechanism by which proteins that carry this signal are subject to degradation, leading to M-current dysfunction, which causes epilepsy.     

Kv7 channels can function without constitutive calmodulin tethering

M-channels are voltage-gated potassium channels composed of Kv7.2-7.5 subunits that serve as important regulators of neuronal excitability. Calmodulin binding is required for Kv7 channel function and mutations in Kv7.2 that disrupt calmodulin binding cause Benign Familial Neonatal Convulsions (BFNC), a dominantly inherited human epilepsy. On the basis that Kv7.2 mutants deficient in calmodulin binding are not functional, calmodulin has been defined as an auxiliary subunit of Kv7 channels. However, we have identified a presumably phosphomimetic mutation S511D that permits calmodulin-independent function. Thus, our data reveal that constitutive tethering of calmodulin is not required for Kv7 channel function.