The Na^+/Ca^(2+) exchanger(NCX) protein family is a part of the cation/Ca^(2+) exchanger superfamily and participates in the regulation of cellular Ca^(2+) homeostasis. NCX1, the most important subtype in the NCX fami...The Na^+/Ca^(2+) exchanger(NCX) protein family is a part of the cation/Ca^(2+) exchanger superfamily and participates in the regulation of cellular Ca^(2+) homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption.This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.展开更多
AIM： Interstitial cells of Cajal （ICCs） are the pacemaker cells that generate slow waves in the gastrointestinal （GI） tract. We have aimed to investigate the involvement of mitochondrial Na^＋-Ca^2＋ exchange in ...AIM： Interstitial cells of Cajal （ICCs） are the pacemaker cells that generate slow waves in the gastrointestinal （GI） tract. We have aimed to investigate the involvement of mitochondrial Na^＋-Ca^2＋ exchange in intestinal pacemaking activity in cultured interstitial cells of Cajal. METHODS： Enzymatic digestions were used to dissociate ICCs from the small intestine of a mouse. The whole-cell patch-clamp configuration was used to record membrane currents （voltage clamp） and potentials （current clamp） from cultured ICCs. RESULTS： Clonazepam and CGP37157 inhibited the pacemaking activity of ICCs in a dose-dependent manner. Clonazepam from 20 to 60 μmol/L and CGP37157 from 10 to 30 μmol/L effectively inhibited Ca^2＋ efflux from mitochondria in pacemaking activity of ICCs. The ICsos of clonazepam and CGP37157 were 37.1 and 18.2 μmol/ L, respectively. The addition of 20 μmol/L NiCl2 to the internal solution caused a ＂wax and wane＂ phenomenon of pacemaking activity of ICCs. CONCLUSION： These results suggest that mitochondria Na^＋-Ca^2＋ exchange has an important role in intestina pacemaking activity.展开更多
The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an i...The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an integral membrane protein that exclusively regulates intracellular pH(pHi)by exchanging one intracellular H1 for one extracellular Na1.However,the role of Nups in cardiac NHE1 expression remains unknown.We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA.The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5′-UTR(2412 to2213 nt)of nhe1mRNA.Nup35 ablationweakensthe resistance of cardiomyocytes to an acid challenge by depressingNHE1 expression.Moreover,we identify thatNup35 andNHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro.Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification.We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression.This finding reveals a novel regulatory mechanism of cardiomyocyte pHi,and may provide insight into the therapeutic strategy for ischemic cardiac diseases.展开更多
Background： Na^＋/Ca^2＋ exchanger （NCX） plays a crucial role in pentylenetetrazol-induced convulsion. However, it is unclear whether NCX is critically involved in hyperthermia-induced convulsion. In this study, we...Background： Na^＋/Ca^2＋ exchanger （NCX） plays a crucial role in pentylenetetrazol-induced convulsion. However, it is unclear whether NCX is critically involved in hyperthermia-induced convulsion. In this study, we examined the potential changes in NCX3 in the hippocampus and cerebrocortex of rats with hyperthermia-induced convulsion. Methods： Twenty-one Sprague Dawley rats were randomly assigned to control group, convulsion-prone group and convulsion-resistant group （n = 7 in each group）. Whole-cell patch-clamp method was used to record NCX currents. Both the Western blotting analysis and immunofluorescence labeling techniques were used to examine the expression of NCX3. Results： NCX currents were decreased in rats after febrile convulsion. Compared to the control group, NCX3 expression was decreased by about 40% and 50% in the hippocampus and cerebrocortex of convulsion-prone rats, respectively. Furthermore, the extent of reduction in NCX3 expression seemed to correlate with the number of seizures. Conclusions： There is a significant reduction in NCX3 expression in rats with febrile convulsions. Our findings also indicate a potential link between NCX3 expression, febrile convulsion in early childhood, and adult onset of epilepsy.展开更多
Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial m...Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases.Despite their importance,identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific.This review will focus on the mitochondrial exchanger,initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX.Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types.In lymphocytes,NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic β cells,and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells.Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes.Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.展开更多
Background：Calcium regulatory proteins-L-type Ca^2＋ channels （LTCCs）,ryanodine receptor 2 （RyR2）,and Na^＋/Ca^2＋ exchanger isoform 1 （NCX1） have been recognized as important protective mechanisms during myoca...Background：Calcium regulatory proteins-L-type Ca^2＋ channels （LTCCs）,ryanodine receptor 2 （RyR2）,and Na^＋/Ca^2＋ exchanger isoform 1 （NCX1） have been recognized as important protective mechanisms during myocardial ischemia-reperfusion injury （I/RI）.Both sevofturane postconditioning （SevoPoC） and delayed remote ischemic preconditioning （DRIPC） have been shown to protect the heart against I/RI.In this study,we aimed to compare the effects of SevoPoC and DRIPC on the expression of the three calcium regulatory proteins in an isolated rat heart model.Methods：After 30-min balanced perfusion,isolated hearts from rats were subjected to 30-min ischemia followed by 60-min reperfusion.Totally 40 isolated hearts were randomly assigned to four groups （n =10/group）：time control group,I/RI group,SevoPoC group,and DRIPC group.The effect of SevoPoC （3% v/v） and DRIPC were observed.Myocardial infarct size （IS）,cardiac troponin I level,and heart function were measured.The protein and messenger RNA levels of LTCCs,RyR2,and NCX1 were determined.Results：Both SevoPoC and DRIPC improved the recovery of myocardial function,and reduced cardiac troponin Ⅰ release after I/RI.The decrease in IS was more significant in the SevoPoC group than that in the DRIPC group （16.50% ± 4.54% in the SevoPoC group [P =0.0006],and 22.34% ± 4.02% in the DRIPC group [P =0.0007] vs.35.00% ± 5.24% in the I/RI group,respectively）.SevoPoC,but not DRIPC significantly inhibited the activity of NCX 1 （0.59 ＋ 0.09 in the I/RI group vs.0.32 ± 0.16 in the SevoPoC group,P =0.006;vs.0.57 ± 0.14 in the DRIPC group,P =0.072）.No statistical significant differences were observed in the expression of LTCCs and RyR2 between SevoPoC and DRIPC.In addition,subsequent correlation analysis showed a significantly positive relationship between the cardiac troponin Ⅰ level and the protein expression ofNCX1 （r =0.505,P =0.023）.Conclusion：SevoPoC may be more effective in the cardioprotection than DRIPC partly due to the deactivation of NCX1.展开更多
Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It...Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.展开更多
基金Supported by the National Natural Science Foundation of China,No.816660412 to Xie R and No.81160265 to Xu JY
文摘The Na^+/Ca^(2+) exchanger(NCX) protein family is a part of the cation/Ca^(2+) exchanger superfamily and participates in the regulation of cellular Ca^(2+) homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption.This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.
基金Supported by the Seoul National University Hospital Research Fund(03-2004-008)Korea Research Foundation Grant funded by Korea Government(MOEHRD,Basic Research Promotion Fund,KRF-2004-041-E00022)BK21 project for medicine,dentistry,and pharmacy
文摘AIM： Interstitial cells of Cajal （ICCs） are the pacemaker cells that generate slow waves in the gastrointestinal （GI） tract. We have aimed to investigate the involvement of mitochondrial Na^＋-Ca^2＋ exchange in intestinal pacemaking activity in cultured interstitial cells of Cajal. METHODS： Enzymatic digestions were used to dissociate ICCs from the small intestine of a mouse. The whole-cell patch-clamp configuration was used to record membrane currents （voltage clamp） and potentials （current clamp） from cultured ICCs. RESULTS： Clonazepam and CGP37157 inhibited the pacemaking activity of ICCs in a dose-dependent manner. Clonazepam from 20 to 60 μmol/L and CGP37157 from 10 to 30 μmol/L effectively inhibited Ca^2＋ efflux from mitochondria in pacemaking activity of ICCs. The ICsos of clonazepam and CGP37157 were 37.1 and 18.2 μmol/ L, respectively. The addition of 20 μmol/L NiCl2 to the internal solution caused a ＂wax and wane＂ phenomenon of pacemaking activity of ICCs. CONCLUSION： These results suggest that mitochondria Na^＋-Ca^2＋ exchange has an important role in intestina pacemaking activity.
基金This work was supported by grants from the National Key Basic Research Program of China(2013CB531100 to Y.-H.C.)the National Natural Science Foundation of China for National Innovative Research Groups(81221001 to Y.-H.C.)+2 种基金the Major International Joint Research Program of China(81120108004 to Y.-H.C.)the Youth Program(81100124 to L.X.)the General Program(81170224 and 81270313 to J.L.and 31271214 to Y.-H.C.)of the National Natural Science Foundation of China.
文摘The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an integral membrane protein that exclusively regulates intracellular pH(pHi)by exchanging one intracellular H1 for one extracellular Na1.However,the role of Nups in cardiac NHE1 expression remains unknown.We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA.The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5′-UTR(2412 to2213 nt)of nhe1mRNA.Nup35 ablationweakensthe resistance of cardiomyocytes to an acid challenge by depressingNHE1 expression.Moreover,we identify thatNup35 andNHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro.Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification.We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression.This finding reveals a novel regulatory mechanism of cardiomyocyte pHi,and may provide insight into the therapeutic strategy for ischemic cardiac diseases.
基金This study wassupported by grants from the Natural Science Foundation Project of Hubei Province （No. 2004ABA234）, Wuhan Morning Program Project （No. 200850731390）, and Project of Wuhan Clinical Medical Research Center in Children＇s Neural Disease （No. 2014-160）.
文摘Background： Na^＋/Ca^2＋ exchanger （NCX） plays a crucial role in pentylenetetrazol-induced convulsion. However, it is unclear whether NCX is critically involved in hyperthermia-induced convulsion. In this study, we examined the potential changes in NCX3 in the hippocampus and cerebrocortex of rats with hyperthermia-induced convulsion. Methods： Twenty-one Sprague Dawley rats were randomly assigned to control group, convulsion-prone group and convulsion-resistant group （n = 7 in each group）. Whole-cell patch-clamp method was used to record NCX currents. Both the Western blotting analysis and immunofluorescence labeling techniques were used to examine the expression of NCX3. Results： NCX currents were decreased in rats after febrile convulsion. Compared to the control group, NCX3 expression was decreased by about 40% and 50% in the hippocampus and cerebrocortex of convulsion-prone rats, respectively. Furthermore, the extent of reduction in NCX3 expression seemed to correlate with the number of seizures. Conclusions： There is a significant reduction in NCX3 expression in rats with febrile convulsions. Our findings also indicate a potential link between NCX3 expression, febrile convulsion in early childhood, and adult onset of epilepsy.
文摘Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases.Despite their importance,identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific.This review will focus on the mitochondrial exchanger,initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX.Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types.In lymphocytes,NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic β cells,and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells.Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes.Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.
文摘Background：Calcium regulatory proteins-L-type Ca^2＋ channels （LTCCs）,ryanodine receptor 2 （RyR2）,and Na^＋/Ca^2＋ exchanger isoform 1 （NCX1） have been recognized as important protective mechanisms during myocardial ischemia-reperfusion injury （I/RI）.Both sevofturane postconditioning （SevoPoC） and delayed remote ischemic preconditioning （DRIPC） have been shown to protect the heart against I/RI.In this study,we aimed to compare the effects of SevoPoC and DRIPC on the expression of the three calcium regulatory proteins in an isolated rat heart model.Methods：After 30-min balanced perfusion,isolated hearts from rats were subjected to 30-min ischemia followed by 60-min reperfusion.Totally 40 isolated hearts were randomly assigned to four groups （n =10/group）：time control group,I/RI group,SevoPoC group,and DRIPC group.The effect of SevoPoC （3% v/v） and DRIPC were observed.Myocardial infarct size （IS）,cardiac troponin I level,and heart function were measured.The protein and messenger RNA levels of LTCCs,RyR2,and NCX1 were determined.Results：Both SevoPoC and DRIPC improved the recovery of myocardial function,and reduced cardiac troponin Ⅰ release after I/RI.The decrease in IS was more significant in the SevoPoC group than that in the DRIPC group （16.50% ± 4.54% in the SevoPoC group [P =0.0006],and 22.34% ± 4.02% in the DRIPC group [P =0.0007] vs.35.00% ± 5.24% in the I/RI group,respectively）.SevoPoC,but not DRIPC significantly inhibited the activity of NCX 1 （0.59 ＋ 0.09 in the I/RI group vs.0.32 ± 0.16 in the SevoPoC group,P =0.006;vs.0.57 ± 0.14 in the DRIPC group,P =0.072）.No statistical significant differences were observed in the expression of LTCCs and RyR2 between SevoPoC and DRIPC.In addition,subsequent correlation analysis showed a significantly positive relationship between the cardiac troponin Ⅰ level and the protein expression ofNCX1 （r =0.505,P =0.023）.Conclusion：SevoPoC may be more effective in the cardioprotection than DRIPC partly due to the deactivation of NCX1.
基金supported by the National Natural Science Foundation of China(30900646 and 81241004)
文摘Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.
