Mitsugumin 29 (MG29) is a transmembrane protein that is normally found in the triad junction of skeletal muscle. Our previous studies have shown that targeted deletion of mg29 from the skeletal muscle resulted in abno...Mitsugumin 29 (MG29) is a transmembrane protein that is normally found in the triad junction of skeletal muscle. Our previous studies have shown that targeted deletion of mg29 from the skeletal muscle resulted in abnormality of the triad junction structure, and also increased susceptibility to muscle fatigue. To elucidate the basis of these effects, we investigated the properties of Ca2+-uptake and -release in toxin-skinned Extensor Digitorium Longus (EDL) muscle fibers from control and mg29 knockout mice. Compared with the control muscle, submaximal Ca2+-uptake into the sarcoplasmic reticulum (SR) was slower and the storage of Ca2+ inside the SR was less in the mutant muscle, due to increased leakage process of Ca2+ movement across the SR. The leakage pathway is associated with the increased sensitivity of Ca2+/caffeine -induced Ca2+ release to myoplasmic Ca2+. Therefore, the increased fatigability of mutant EDL muscles can result from a combination of a slowing of Ca2+ uptake, modification of Ca2+-induced Ca2+ release (CICR), and a reduction in total SR Ca2+ content.展开更多
Signal transduction is an important and basic mechanism to cell life activities.The stochastic state transition of receptor induces the release of signaling molecular,which triggers the state transition of other recep...Signal transduction is an important and basic mechanism to cell life activities.The stochastic state transition of receptor induces the release of signaling molecular,which triggers the state transition of other receptors.It constructs a nonlinear sigaling network,and leads to robust switchlike properties which are critical to biological function.Network architectures and state transitions of receptor affect the performance of this biological network.In this work,we perform a study of nonlinear signaling on biological polymorphic network by analyzing network dynamics of the Ca^(2+)-induced Ca^(2+)release(CICR)mechanism,where fast and slow processes are involved and the receptor has four conformational states.Three types of networks,Erdos–R´enyi(ER)network,Watts–Strogatz(WS)network,and BaraB´asi–Albert(BA)network,are considered with different parameters.The dynamics of the biological networks exhibit different patterns at different time scales.At short time scale,the second open state is essential to reproduce the quasi-bistable regime,which emerges at a critical strength of connection for all three states involved in the fast processes and disappears at another critical point.The pattern at short time scale is not sensitive to the network architecture.At long time scale,only monostable regime is observed,and difference of network architectures affects the results more seriously.Our finding identifies features of nonlinear signaling networks with multistate that may underlie their biological function.展开更多
This study addresses the fundamental principle of inter-synaptic interactions in synaptic cross-talk through homosynaptic and heterosynaptic plasticity by studying the intrinsic calcium signaling dynamics in spines. B...This study addresses the fundamental principle of inter-synaptic interactions in synaptic cross-talk through homosynaptic and heterosynaptic plasticity by studying the intrinsic calcium signaling dynamics in spines. Beyond the calcium influx into synapse through voltage gated calcium channels （VGCCs） and N-methyl-D-aspartate （NNMDA） receptors, the function of calcium released from internal store in mediating inter-synaptic cross-talk has barely been modeled. This work investigates how different sources of calcium contribute to inter-synaptic cross-talk and synaptic clustering. Based on experimental observations, we developed a mathematical model in one dimensional system with uniform distribution of spines with the connected dendrite. We modeled the biophysical process of calcium induced calcium release （CICR） in the dendritic smooth endoplasmic reticulum （SER）. Our model compared distinct roles of calcium diffusion, back propagated action potentials （bAPs） and CICR played in synaptic clustering and inter-synaptic cross-talk. The simulation result demonstrated that calcium signal extruded from spine into dendrite requires amplification by CICR before invading neighboring spines to induce plasticity. Our model predicted that initial calcium concentration in SER may discriminate between different types of neuronal activity and induce completely different synaptic potentiation and depression.展开更多
The most prominent ion channel localized in plant vacuoles is the slow activating SV type. Slow vacuolar （SV） channels were discovered by patch clamp studies as early as 1986. In the following two decades, numerous ...The most prominent ion channel localized in plant vacuoles is the slow activating SV type. Slow vacuolar （SV） channels were discovered by patch clamp studies as early as 1986. In the following two decades, numerous studies revealed that these calcium- and voltage-activated, nonselective cation channels are expressed in the vacuoles of all plants and every plant tissue. The voltage-dependent properties of the SV channel are susceptible to modulation by calcium, pH, redox state, as well as regulatory proteins. In Arabidopsis, the SV channel is encoded by the AtTPC1 gene, and even though its gene product represents the by far largest conductance of the vacuolar membrane, tpcl-loss-of-function mutants appeared not to be impaired in major physiological functions such as growth, development, and reproduction. In contrast, the fou2 gain-of-function point mutation D454N within TPC1 leads to a pronounced growth phenotype and increased synthesis of the stress hormone jasmonate. Since the TPC1 gene is present in all land plants, it likely encodes a very general function. In this review, we will discuss major SV channel properties and their impact on plant cell physiology.展开更多
目的分析重组人促红素(recombinant human erythropoietin,rhEPO)各等电点异构体分子体内活性强度(单位时间单位摩尔量下产生体内活性量),找出最适作用分子。方法根据rhEPO等电点异构体体内比活性数据变化,构建等电点异构体分子与其体...目的分析重组人促红素(recombinant human erythropoietin,rhEPO)各等电点异构体分子体内活性强度(单位时间单位摩尔量下产生体内活性量),找出最适作用分子。方法根据rhEPO等电点异构体体内比活性数据变化,构建等电点异构体分子与其体内活性之间关系的数学模型,并进行解析。结果得到rhEPO等电点异构体分子体内活性与唾液酸数量关系:Si=0.628·e^(i-10)·(|i-10|+1)^-2+0.492,R^2>0.9880(i为正整数且16>i>8,表示rhEPO分子上唾液酸数量;Si表示某等电点异构体体内比活性,体内比活性单位10^5 IU/mg),在此基础上,进而提出rhEPO与其受体相互作用模型假说(电荷识别-分子内氢键重排-构象变化-排斥解离假说)。结论通过对rhEPO等电点异质性与体内比活性关系的进一步分析,阐述了rhEPO与其受体相互作用存在最适作用分子,并依据上述实验和数据分析提出了rhEPO与其受体相互作用的模型假说,为rhEPO体内和体外活性的研究提供了思路。展开更多
Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process.Amyloid plaques,neurofibrillary tan...Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process.Amyloid plaques,neurofibrillary tangles and neuronal loss,though characteristic of AD,are late stage markers whose impact on the most devastating aspect of AD,namely memory loss and cognitive deficits,are still unclear.Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline.One common element that presents with several features of AD is disrupted neuronal calcium signaling.Increased intracellular calcium levels are functionally linked to presenilin mutations,ApoE4 expression,amyloid plaques,tau tangles and synaptic dysfunction.In this review,we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.展开更多
Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and ...Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and activated the L-type Ca2+ channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca2+]i elevation was abolished in the presence of the ETA receptor blocker BQ123, but was not affected by the ETB receptor blocker BQ788. ET-1-induced an increase in [Ca2+]i, which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 μmol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca2+]i increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca2+ channel current and an increase of open-state probability (NPo) of an L-type single Ca2+ channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca2+ channel activation and Ca2+-induced Ca2+ release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.展开更多
基金supported by the NIH-NIA Minority Faculty Training Grant and Supplemental Grant Award(AG-15556)(to M.Brotto and J.Ma,respectively)The American Heart Association(Ohio Valley Affiliate)postdoctoral fellowship(to R.Nagaraj),by the National Institutes of Health Grant HL-60304(to T.M.Nosek and M.Brotto)grants AG-15556 and CA-95739(to J.Ma).
文摘Mitsugumin 29 (MG29) is a transmembrane protein that is normally found in the triad junction of skeletal muscle. Our previous studies have shown that targeted deletion of mg29 from the skeletal muscle resulted in abnormality of the triad junction structure, and also increased susceptibility to muscle fatigue. To elucidate the basis of these effects, we investigated the properties of Ca2+-uptake and -release in toxin-skinned Extensor Digitorium Longus (EDL) muscle fibers from control and mg29 knockout mice. Compared with the control muscle, submaximal Ca2+-uptake into the sarcoplasmic reticulum (SR) was slower and the storage of Ca2+ inside the SR was less in the mutant muscle, due to increased leakage process of Ca2+ movement across the SR. The leakage pathway is associated with the increased sensitivity of Ca2+/caffeine -induced Ca2+ release to myoplasmic Ca2+. Therefore, the increased fatigability of mutant EDL muscles can result from a combination of a slowing of Ca2+ uptake, modification of Ca2+-induced Ca2+ release (CICR), and a reduction in total SR Ca2+ content.
基金Project supported by the National Natural Science Foundation of China(Grant No.11675228)China Postdoctoral Science Foundation(Grant No.2015M572662XB).
文摘Signal transduction is an important and basic mechanism to cell life activities.The stochastic state transition of receptor induces the release of signaling molecular,which triggers the state transition of other receptors.It constructs a nonlinear sigaling network,and leads to robust switchlike properties which are critical to biological function.Network architectures and state transitions of receptor affect the performance of this biological network.In this work,we perform a study of nonlinear signaling on biological polymorphic network by analyzing network dynamics of the Ca^(2+)-induced Ca^(2+)release(CICR)mechanism,where fast and slow processes are involved and the receptor has four conformational states.Three types of networks,Erdos–R´enyi(ER)network,Watts–Strogatz(WS)network,and BaraB´asi–Albert(BA)network,are considered with different parameters.The dynamics of the biological networks exhibit different patterns at different time scales.At short time scale,the second open state is essential to reproduce the quasi-bistable regime,which emerges at a critical strength of connection for all three states involved in the fast processes and disappears at another critical point.The pattern at short time scale is not sensitive to the network architecture.At long time scale,only monostable regime is observed,and difference of network architectures affects the results more seriously.Our finding identifies features of nonlinear signaling networks with multistate that may underlie their biological function.
基金We would like to thank Prof. Florentin Woergoetter, Dr. Christian Tetzlaff and Dr. Tomas Kulvicius for helpful discussions. This work is supported by Chinese Natural Science Foundation with 31601145, the Fundamental Research Funds for the Central Universities, and the Federal Ministry of Education and Research （BMBF） Germany to the Goettingen Bernstein Center for Computational Neuroscience Project D1. Y.L. conceived the experiment（s）, Z.Z. and Y.L. conducted the experiment（s）, Y.L. and Z.Z. analyzed the results, Y.L. wrote the paper. All authors reviewed the manuscript. The authors declare no competing interest.
文摘This study addresses the fundamental principle of inter-synaptic interactions in synaptic cross-talk through homosynaptic and heterosynaptic plasticity by studying the intrinsic calcium signaling dynamics in spines. Beyond the calcium influx into synapse through voltage gated calcium channels （VGCCs） and N-methyl-D-aspartate （NNMDA） receptors, the function of calcium released from internal store in mediating inter-synaptic cross-talk has barely been modeled. This work investigates how different sources of calcium contribute to inter-synaptic cross-talk and synaptic clustering. Based on experimental observations, we developed a mathematical model in one dimensional system with uniform distribution of spines with the connected dendrite. We modeled the biophysical process of calcium induced calcium release （CICR） in the dendritic smooth endoplasmic reticulum （SER）. Our model compared distinct roles of calcium diffusion, back propagated action potentials （bAPs） and CICR played in synaptic clustering and inter-synaptic cross-talk. The simulation result demonstrated that calcium signal extruded from spine into dendrite requires amplification by CICR before invading neighboring spines to induce plasticity. Our model predicted that initial calcium concentration in SER may discriminate between different types of neuronal activity and induce completely different synaptic potentiation and depression.
文摘The most prominent ion channel localized in plant vacuoles is the slow activating SV type. Slow vacuolar （SV） channels were discovered by patch clamp studies as early as 1986. In the following two decades, numerous studies revealed that these calcium- and voltage-activated, nonselective cation channels are expressed in the vacuoles of all plants and every plant tissue. The voltage-dependent properties of the SV channel are susceptible to modulation by calcium, pH, redox state, as well as regulatory proteins. In Arabidopsis, the SV channel is encoded by the AtTPC1 gene, and even though its gene product represents the by far largest conductance of the vacuolar membrane, tpcl-loss-of-function mutants appeared not to be impaired in major physiological functions such as growth, development, and reproduction. In contrast, the fou2 gain-of-function point mutation D454N within TPC1 leads to a pronounced growth phenotype and increased synthesis of the stress hormone jasmonate. Since the TPC1 gene is present in all land plants, it likely encodes a very general function. In this review, we will discuss major SV channel properties and their impact on plant cell physiology.
文摘目的分析重组人促红素(recombinant human erythropoietin,rhEPO)各等电点异构体分子体内活性强度(单位时间单位摩尔量下产生体内活性量),找出最适作用分子。方法根据rhEPO等电点异构体体内比活性数据变化,构建等电点异构体分子与其体内活性之间关系的数学模型,并进行解析。结果得到rhEPO等电点异构体分子体内活性与唾液酸数量关系:Si=0.628·e^(i-10)·(|i-10|+1)^-2+0.492,R^2>0.9880(i为正整数且16>i>8,表示rhEPO分子上唾液酸数量;Si表示某等电点异构体体内比活性,体内比活性单位10^5 IU/mg),在此基础上,进而提出rhEPO与其受体相互作用模型假说(电荷识别-分子内氢键重排-构象变化-排斥解离假说)。结论通过对rhEPO等电点异质性与体内比活性关系的进一步分析,阐述了rhEPO与其受体相互作用存在最适作用分子,并依据上述实验和数据分析提出了rhEPO与其受体相互作用的模型假说,为rhEPO体内和体外活性的研究提供了思路。
文摘Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process.Amyloid plaques,neurofibrillary tangles and neuronal loss,though characteristic of AD,are late stage markers whose impact on the most devastating aspect of AD,namely memory loss and cognitive deficits,are still unclear.Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline.One common element that presents with several features of AD is disrupted neuronal calcium signaling.Increased intracellular calcium levels are functionally linked to presenilin mutations,ApoE4 expression,amyloid plaques,tau tangles and synaptic dysfunction.In this review,we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.
基金Supported by the National Natural Science Foundation of China (Grant No. 200830870910).
文摘Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and activated the L-type Ca2+ channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca2+]i elevation was abolished in the presence of the ETA receptor blocker BQ123, but was not affected by the ETB receptor blocker BQ788. ET-1-induced an increase in [Ca2+]i, which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 μmol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca2+]i increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca2+ channel current and an increase of open-state probability (NPo) of an L-type single Ca2+ channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca2+ channel activation and Ca2+-induced Ca2+ release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.
