Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src

Apolipoprotein CIII (ApoCIII) not only serves as an inhibitor of triglyceride hydrolysis but also participates in diabetes-related pathological events such as hyperactivation of voltage-gated Ca²⁺ (Ca_V) channels in the pancreatic β cell. However, nothing is known about the molecular mechanisms whereby ApoCIII hyperactivates β cell Ca_V channels. We now demonstrate that ApoCIII increased Ca_V1 channel open probability and density. ApoCIII enhanced whole-cell Ca²⁺ currents and the Ca_V1 channel blocker nimodipine completely abrogated this enhancement. The effect of ApoCIII was not influenced by individual inhibition of PKA, PKC, or Src. However, combined inhibition of PKA, PKC, and Src counteracted the effect of ApoCIII, similar results obtained by coinhibition of PKA and Src. Moreover, knockdown of β1 integrin or scavenger receptor class B type I (SR-BI) prevented ApoCIII from hyperactivating β cell Ca_V channels. These data reveal that ApoCIII hyperactivates β cell Ca_V1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src.     

Gating pore current in an inherited ion channelopathy

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Na(V)1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies.     

The chick ovomucoid gene contains at least six intervening sequences.

A 15-kilobase pair EcoRI chick DNA fragment, containing both the termination codon UGA and the 5'-portion of the structural ovomucoid gene, has been cloned in lambda phage Charon 4A by in vitro packaging. Restriction mapping and electron microscopic analyses of this cloned DNA have revealed that the structural ovomucoid gene sequences are separated by at least six intervening sequences.     

Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP

Bivalve molluscs, the primary vectors of paralytic shellfish poisoning (PSP) in humans, show marked inter-species variation in their capacity to accumulate PSP toxins (PSTs) which has a neural basis. PSTs cause human fatalities by blocking sodium conductance in nerve fibres. Here we identify a molecular basis for inter-population variation in PSP resistance within a species, consistent with genetic adaptation to PSTs. Softshell clams (Mya arenaria) from areas exposed to 'red tides' are more resistant to PSTs, as demonstrated by whole-nerve assays, and accumulate toxins at greater rates than sensitive clams from unexposed areas. PSTs lead to selective mortality of sensitive clams. Resistance is caused by natural mutation of a single amino acid residue, which causes a 1,000-fold decrease in affinity at the saxitoxin-binding site in the sodium channel pore of resistant, but not sensitive, clams. Thus PSTs might act as potent natural selection agents, leading to greater toxin resistance in clam populations and increased risk of PSP in humans. Furthermore, global expansion of PSP to previously unaffected coastal areas might result in long-term changes to communities and ecosystems.     

Crystal structure of a voltage-gated sodium channel in two potentially inactivated states

In excitable cells, voltage-gated sodium (Na(V)) channels activate to initiate action potentials and then undergo fast and slow inactivation processes that terminate their ionic conductance. Inactivation is a hallmark of Na(V) channel function and is critical for control of membrane excitability, but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type Na(V)Ab channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2?? resolution. Compared to previous structures of Na(V)Ab channels with cysteine mutations in the pore-lining S6 helices (ref. 4), the S6 helices and the intracellular activation gate have undergone significant rearrangements: one pair of S6 helices has collapsed towards the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type Na(V)Ab models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues that are analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains have also shifted around the perimeter of the pore module in wild-type Na(V)Ab, compared to the mutant channel, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in Na(V) channel gating and inactivation. These potential inactivated-state structures provide new insights into Na(V) channel gating and novel avenues to drug development and therapy for a range of debilitating Na(V) channelopathies.     

国学的术语规范问题

国学的术语规范指的是国学所属各学科的术语规范。国学术语的规范既是术语学和国学的研究对象,也是语言规划的重要内容,同时它还是建设有中国特色术语学的重要组成部分。文章从国学术语的概念划分、科学定义、术语定名和译介等方面对国学的术语规范问题作了系统阐述。     

人工关节材料及其表面改性研究进展

人工关节是替代病变或损伤关节的植入性假体,除了应满足生物相容性要求外,必须具备足够的抗磨损能力。本文综述了目前使用的不同人工关节材料的性能,以及为提高抗磨损能力而对各种材料进行改性处理的新方法,提出在人工关节表面加工微纳结构来提高其抗磨损性能和生物相容性的新思路。     

基于小波与BP神经网络的太阳黑子时间序列分析预测

太阳黑子年平均数序列是典型的非线性、复杂时间序列.本文利用小波变换,将太阳黑子年平均数序列进行分解重构,对信号的周期特性进行分析,然后采用BP神经网络对重构信号进行预测,建立太阳黑子年平均数的预测序列.结果表明,该模型具有较高的预测精度.     

山西省R＆D经费投入状况分析

通过对山西省R&D经费投入状况的分析,指出了其不足与存在的问题,并进一步提出应加大山西省R&D经费投入力度,使R&D活动真正成为促进山西省经济发展的主要动力。     

浅谈居住小区规划技术标准的修改

针对当前《城市居住区规划设计规划》中部分指标老化给居住小区规划带来的负面影响,分别分析了城市居住小区户均人口下降、人均居住用地指标增大、机动车交通迅速增长、城市社会人口年龄结构变化以及人们日常生活需求的变化对小区规划产生的影响,指出应相应调整《规范》中关于小区规模、道路与停车设施、配套公共设施及小区绿地的规划设计指标,并应进一步完善指标体系,从而使小区规划更科学合理。