To investigate the mechanisms of microwave induced pacemaker cell injuries, Wistar rats and the primary pacemaker cells of newborn Wistar rats were exposed to microwave at average power density of 50 mW/cm2. Slower sp...To investigate the mechanisms of microwave induced pacemaker cell injuries, Wistar rats and the primary pacemaker cells of newborn Wistar rats were exposed to microwave at average power density of 50 mW/cm2. Slower spontaneous beating rate, intercellular Ca2＋ aggregation and cell membrane perforation were detected immediately after the exposure. Moreover, hyperpolarizationactivated cyclic nucleotide-gated cation channel 4 （HCN4） was down-regulated immediately after the exposure and up-regulated at 12 h after the exposure. In the sinoatrial node （SAN） of the rats,展开更多
Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled ...Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled the molecular identity of HCN (HCN1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ⅰh and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.展开更多
Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unv...Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unveiled the molecular identity of HCN (HCN 1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in the development of biological pacemakers.展开更多
The action potential of pacemaker cells in the sino-atrial node forms the automatic rhythm of the heart. The automatic depolarization in phase 4 is me DaSlS of the automaticity in pacemaker cells. Many currents are in...The action potential of pacemaker cells in the sino-atrial node forms the automatic rhythm of the heart. The automatic depolarization in phase 4 is me DaSlS of the automaticity in pacemaker cells. Many currents are included in phase 4, such as calcium current, TTX-sensitive sodium current, sustained inward current （Isi）, decay of delayed rectifier potassium current, etc. Funny current （If） has long been recognized as important in this phase and is activated at hyperpolarized potentials during cell diastole and in turn activates other currents to form automatic depolarization.展开更多
Since the first plant cyclic nucleotide-gated ion channel （CNGC）, HvCBT1, was identified as a calmodulin bind- ing protein, more than a decade has passed and a substantial amount of work has been done to understand ...Since the first plant cyclic nucleotide-gated ion channel （CNGC）, HvCBT1, was identified as a calmodulin bind- ing protein, more than a decade has passed and a substantial amount of work has been done to understand the molecular nature and function of these channel proteins. Based on electrophysiological and heterologous expression analyses, plant CNGCs function as non-selective cation channels and, so far, their biological roles have been reported in defense responses, development, and ion homeostasis. Forward genetic approaches identified four AtCNGCs （AtCNGC2, 4, 11, and 12） to be involved in plant immunity, as null mutants for AtCNGC2, 4, 11, and 12 as well as a gain-of- function mutant for AtCNGC11 and 12 exhibited alterations in defense responses. Since ion flux changes have been reported as one of the early events upon pathogen recognition and also are an essential component for the activation of defense responses, the involvement of CNGCs in these ion flux changes has been suggested. However, the recent detailed characterization of null mutants suggested a more complex involvement of this channel family. In this review, we focus on the discoveries and character- ization of these CNGC mutants and discuss possible roles of CNGCs as components in plant immunity.展开更多
We recently found that growth factor receptor-bound(Grb)protein 14 is a novel physiological modulator of photoreceptor specific cyclic nucleotide-gated channel alpha subunit(CNGA1).Grb14 promotes the CNG channel closu...We recently found that growth factor receptor-bound(Grb)protein 14 is a novel physiological modulator of photoreceptor specific cyclic nucleotide-gated channel alpha subunit(CNGA1).Grb14 promotes the CNG channel closure through its Ras-associating(RA)domain.In the current study we show that this RA domain-mediated inhibition of rod CNG channel is electrostatic in nature.Grb14 competes with cGMP for the CNGA1 binding pocket and electrostatically interacts with Arg^(559) through a negatively chargedβ-turn at its RA domain.Moreover,the three Glu residues(180–182)in Grb14 are absolutely critical for electrostatic interaction with the cGMP binding pocket and resultant inhibition.Our study also demonstrates that substitution of Lys^(140) for Ala or in combination with polyglutamte mutants of Grb14 results in a significantly reduced binding with CNGA1.These results suggest that in addition to Glu^(180–182) and Lys^(140),other residues in Grb14 may be involved in the electrostatic interaction with CNGA1.The RA domain is highly conserved among the members of Grb7 family of proteins,which includes Grb7,Grb10 and Grb14.Further,only Grb14 is able to modulate the channel activity,but not Grb7 and Grb10.All together,it suggests the existence of a divergence in RA domains among the members of the Grb7 family.展开更多
AIM:To investigate the effects of ZD 7288,a hyperpolarization-activated cyclic nucleotide-gated(HCN)channel blocker,on rats with chronic visceral pain.METHODS:Rats with visceral hypersensitivity were generated using n...AIM:To investigate the effects of ZD 7288,a hyperpolarization-activated cyclic nucleotide-gated(HCN)channel blocker,on rats with chronic visceral pain.METHODS:Rats with visceral hypersensitivity were generated using neonatal colon irritation during postnatal days 8-15 as described previously.Visceral hypersensitivity was evaluated using electromyographic(EMG)responses of abdominal external oblique muscles to 20-80 mmHg colorectal distentions(CRD).Abdominal withdrawal reflex(AWR)scores and pain thresholds were also detected in adult rats.Different doses of ZD7288(25,50,and 100 nmol/L)were intrathecally administered in rats to study the role of spinal HCN channel in chronic visceral hypersensitivity.RESULTS:EMG responses to 20-80 mmHg CRD and AWR scores under 20-60 mmHg CRD significantly increased in rats with visceral hypersensitivity compared to control rats(P<0.05).The pain threshold in rats with visceral hypersensitivity significantly decreased compared to control rats(P<0.05).Treatment with50-100 nmol/L ZD 7288 significantly inhibited EMG responses(16%-62%,80-20 mmHg CRD,P<0.05)and AWR scores(24%-37%,40-20 mmHg CRD,P<0.05;12%-61%,80-20 mmHg CRD,P<0.05,respectively),and significantly increased pain thresholds(32%-77%,P<0.05).CONCLUSION:Spinal HCN channels may play an important role in chronic visceral hypersensitivity.展开更多
环核苷酸门控离子通道（cyclic nucleotide-gated ion channels,CNG）是非选择性的阳离子通道,直接被环核苷酸活化.6个不同基因编码CNG离子通道蛋白,4个A亚单元（A1～A4）和2个B亚单元（B1,B3）.CNG离子通道是由2个或3个不同的亚单元组...环核苷酸门控离子通道（cyclic nucleotide-gated ion channels,CNG）是非选择性的阳离子通道,直接被环核苷酸活化.6个不同基因编码CNG离子通道蛋白,4个A亚单元（A1～A4）和2个B亚单元（B1,B3）.CNG离子通道是由2个或3个不同的亚单元组成的异四聚体复合物,是Ca^2＋进入细胞内的主要通道之一.CNG离子通道的活性可被Ca^2＋/CaM及磷酸化/去磷酸化作用所调节,从而改变细胞内钙离子浓度,触发一系列生理效应.近年来CNG离子通道的研究进展神速,成为生命科学的一个热点领域.本文对CNG离子通道的结构、功能及活性调节机制进行了综述.展开更多
文摘To investigate the mechanisms of microwave induced pacemaker cell injuries, Wistar rats and the primary pacemaker cells of newborn Wistar rats were exposed to microwave at average power density of 50 mW/cm2. Slower spontaneous beating rate, intercellular Ca2＋ aggregation and cell membrane perforation were detected immediately after the exposure. Moreover, hyperpolarizationactivated cyclic nucleotide-gated cation channel 4 （HCN4） was down-regulated immediately after the exposure and up-regulated at 12 h after the exposure. In the sinoatrial node （SAN） of the rats,
基金the National Natural Science Foundation of China(No.30470559,30330230,30240059)the National Basic Research Development Program(973)of China(No.2007CB512501)Beijing Natural Science Foundation(No.7052039)
文摘Dorsal root ganglion(DRG)neurons have peripheral terminals in skin,muscle,and other peripheral tissues,andcentral
文摘Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled the molecular identity of HCN (HCN1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ⅰh and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.
文摘Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unveiled the molecular identity of HCN (HCN 1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in the development of biological pacemakers.
基金This study was supported by the grants from the National"863"Program(No.2001AA2160313)Beijing Important Program Fund of Science and Technology(No.H020220010490)Capital Medical Development Fund of Science and Technology(No.2003-3002)
文摘The action potential of pacemaker cells in the sino-atrial node forms the automatic rhythm of the heart. The automatic depolarization in phase 4 is me DaSlS of the automaticity in pacemaker cells. Many currents are included in phase 4, such as calcium current, TTX-sensitive sodium current, sustained inward current （Isi）, decay of delayed rectifier potassium current, etc. Funny current （If） has long been recognized as important in this phase and is activated at hyperpolarized potentials during cell diastole and in turn activates other currents to form automatic depolarization.
文摘Since the first plant cyclic nucleotide-gated ion channel （CNGC）, HvCBT1, was identified as a calmodulin bind- ing protein, more than a decade has passed and a substantial amount of work has been done to understand the molecular nature and function of these channel proteins. Based on electrophysiological and heterologous expression analyses, plant CNGCs function as non-selective cation channels and, so far, their biological roles have been reported in defense responses, development, and ion homeostasis. Forward genetic approaches identified four AtCNGCs （AtCNGC2, 4, 11, and 12） to be involved in plant immunity, as null mutants for AtCNGC2, 4, 11, and 12 as well as a gain-of- function mutant for AtCNGC11 and 12 exhibited alterations in defense responses. Since ion flux changes have been reported as one of the early events upon pathogen recognition and also are an essential component for the activation of defense responses, the involvement of CNGCs in these ion flux changes has been suggested. However, the recent detailed characterization of null mutants suggested a more complex involvement of this channel family. In this review, we focus on the discoveries and character- ization of these CNGC mutants and discuss possible roles of CNGCs as components in plant immunity.
基金by grants from the NIH(EY016507EY00871EY12190).CNGA1 and CNGB1 subunit channel antibodies were a kind gift from Dr.Robert Molday,University of British Columbia(Canada).
文摘We recently found that growth factor receptor-bound(Grb)protein 14 is a novel physiological modulator of photoreceptor specific cyclic nucleotide-gated channel alpha subunit(CNGA1).Grb14 promotes the CNG channel closure through its Ras-associating(RA)domain.In the current study we show that this RA domain-mediated inhibition of rod CNG channel is electrostatic in nature.Grb14 competes with cGMP for the CNGA1 binding pocket and electrostatically interacts with Arg^(559) through a negatively chargedβ-turn at its RA domain.Moreover,the three Glu residues(180–182)in Grb14 are absolutely critical for electrostatic interaction with the cGMP binding pocket and resultant inhibition.Our study also demonstrates that substitution of Lys^(140) for Ala or in combination with polyglutamte mutants of Grb14 results in a significantly reduced binding with CNGA1.These results suggest that in addition to Glu^(180–182) and Lys^(140),other residues in Grb14 may be involved in the electrostatic interaction with CNGA1.The RA domain is highly conserved among the members of Grb7 family of proteins,which includes Grb7,Grb10 and Grb14.Further,only Grb14 is able to modulate the channel activity,but not Grb7 and Grb10.All together,it suggests the existence of a divergence in RA domains among the members of the Grb7 family.
基金Supported by The Natural Science Fund of Fujian Province,No.C0910595 and No.2012J05053Science Fund and Doctor Initial Fund of FMU,No.09ZD009 and No.2010BS008
文摘AIM:To investigate the effects of ZD 7288,a hyperpolarization-activated cyclic nucleotide-gated(HCN)channel blocker,on rats with chronic visceral pain.METHODS:Rats with visceral hypersensitivity were generated using neonatal colon irritation during postnatal days 8-15 as described previously.Visceral hypersensitivity was evaluated using electromyographic(EMG)responses of abdominal external oblique muscles to 20-80 mmHg colorectal distentions(CRD).Abdominal withdrawal reflex(AWR)scores and pain thresholds were also detected in adult rats.Different doses of ZD7288(25,50,and 100 nmol/L)were intrathecally administered in rats to study the role of spinal HCN channel in chronic visceral hypersensitivity.RESULTS:EMG responses to 20-80 mmHg CRD and AWR scores under 20-60 mmHg CRD significantly increased in rats with visceral hypersensitivity compared to control rats(P<0.05).The pain threshold in rats with visceral hypersensitivity significantly decreased compared to control rats(P<0.05).Treatment with50-100 nmol/L ZD 7288 significantly inhibited EMG responses(16%-62%,80-20 mmHg CRD,P<0.05)and AWR scores(24%-37%,40-20 mmHg CRD,P<0.05;12%-61%,80-20 mmHg CRD,P<0.05,respectively),and significantly increased pain thresholds(32%-77%,P<0.05).CONCLUSION:Spinal HCN channels may play an important role in chronic visceral hypersensitivity.
文摘环核苷酸门控离子通道（cyclic nucleotide-gated ion channels,CNG）是非选择性的阳离子通道,直接被环核苷酸活化.6个不同基因编码CNG离子通道蛋白,4个A亚单元（A1～A4）和2个B亚单元（B1,B3）.CNG离子通道是由2个或3个不同的亚单元组成的异四聚体复合物,是Ca^2＋进入细胞内的主要通道之一.CNG离子通道的活性可被Ca^2＋/CaM及磷酸化/去磷酸化作用所调节,从而改变细胞内钙离子浓度,触发一系列生理效应.近年来CNG离子通道的研究进展神速,成为生命科学的一个热点领域.本文对CNG离子通道的结构、功能及活性调节机制进行了综述.
