Plasma membrane Ca2+pumps(PMCA)play a major role in Ca2+homeostasis and signaling by extruding cellular Ca2+with high affinity.PMCA isoforms are encoded by four genes which are expressed differentially in various cell...Plasma membrane Ca2+pumps(PMCA)play a major role in Ca2+homeostasis and signaling by extruding cellular Ca2+with high affinity.PMCA isoforms are encoded by four genes which are expressed differentially in various cell types in normal and disease states.Therefore, PMCA isoform selective inhibitors would aid in delineating their role in physiology and pathophysiology.We are testing the hypothesis that extracellular domains of PMCA can be used as allosteric targets to obtain a novel class of PMCA-specific inhibitors termed caloxins. This review presents the concepts behind the invention of caloxins and our progress in this area.A section is also devoted to the applications of caloxins in literature. We anticipate that isoform-selective caloxins will aid in understanding PMCA physiology in health and disease. With strategies to develop therapeutics from bioactive peptides,caloxins may become clinically useful in car diovascular diseases,neurological disorders,retinopathy,cancer and contraception.展开更多
The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic me...The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic metabolism,has the capacity to cause ATP depletion and thus inhibit PMCA activity.This has potentially fatal consequences,particularly for non-excitable cells in which the PMCA is the major Ca2+efflux pathway.This is because inhibition of the PMCA inevitably leads to cytosolic Ca2+ overload and the consequent cell death.However,the relationship between metabolic stress,ATP depletion and inhibition of the PMCA is not as simple as one would have originally predicted.There is increasing evidence that metabolic stress can lead to the inhibition of PMCA activity independent of ATP or prior to substantial ATP depletion.In particular,there is evidence that the PMCA has its own glycolytic ATP supply that can fuel the PMCA in the face of impaired mitochondrial function.Moreover, membrane phospholipids,mitochondrial membrane potential,caspase/calpain cleavage and oxidative stress have all been implicated in metabolic stress-induced inhibition of the PMCA.The major focus of this review is to challenge the conventional view of ATP-dependent regulation of the PMCA and bring together some of the alternative or additional mechanisms by which metabolic stress impairs PMCA activity resulting in cytosolic Ca2+ overload and cytotoxicity.展开更多
The regulatory mechanisms of cytoplasmic Ca2＋ after myocardial infarction-induced Ca2＋ overload involve secretory pathway Ca2＋-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi ...The regulatory mechanisms of cytoplasmic Ca2＋ after myocardial infarction-induced Ca2＋ overload involve secretory pathway Ca2＋-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi apparatus on Ca2＋ overload after cerebral ischemia and reperfusion remains unclear. Four-vessel occlusion rats were used as animal models of cerebral ischemia. The expression of secretory pathway Ca2＋-ATPase 1 in the cortex and hippocampus was detected by immunoblotting, and Ca2＋ concentrations in the cytoplasm and Golgi vesicles were determined. Results showed an overload of cytoplasmic Ca2＋ during ischemia and reperfusion that reached a peak after reperfusion. Levels of Golgi Ca2＋ showed an opposite effect. The expression of Golgi-specific secretory pathway Ca2＋-ATPase 1 in the cortex and hippocampus decreased before ischemia and reperfusion, and increased after reperfusion for 6 hours. This variation was similar to the alteration of calcium in separated Golgi vesicles. These results indicate that the Golgi apparatus participates in the formation and alleviation of calcium overload, and that secretory pathway Ca2＋-ATPase 1 tightly responds to ischemia and reperfusion in nerve cells. Thus, we concluded that secretory pathway Ca2＋-ATPase 1 plays an essential role in cytosolic calcium regulation and its expression can be used as a marker of Golgi stress, responding to cerebral ischemia and reperfusion. The secretory pathway Ca2＋-ATPase 1 can be an important neuroprotective target of ischemic stroke.展开更多
In order to study the pathogenesis of hypertension associated with noninsulin dependent diabetes mellitus (NIDDM), Plasma glucose, insulin levels at fasting and following an oral glucose load were measured. Na +K +pum...In order to study the pathogenesis of hypertension associated with noninsulin dependent diabetes mellitus (NIDDM), Plasma glucose, insulin levels at fasting and following an oral glucose load were measured. Na +K +pump and Ca 2+ pump activities of red blood cell membrane were also assessed. Hypertensive patients with normal or impaired glucose tolerance (NGT, or IGT) had hyperinsulinemia. Obese hypertensive patients also had hyperinsulinemia, while nonobese hypertensive patients had no hyperinsulinemia, but exhibited a delay in insulin response to oral glucose tolerance test (OGTT). In multivariate analysis, considering the factors of age, BMI and plasma glucose level, DBP were still positively related to both 30 min insulin level and IAUC, but negatively correlated to activities of Na +K +pump and Ca 2+ pump. These results demonstrated that a link between obesity, hpertension and NIDDM is the insulin resistance and/or hyperinsulinemia.展开更多
Previously we have shown that 4 Hz and 8 Hz EMF exposures have depressing effect on the thermodynamic activity of water, which decreases peroxide formation. It has also been shown that 4 Hz EMF-treated physiological s...Previously we have shown that 4 Hz and 8 Hz EMF exposures have depressing effect on the thermodynamic activity of water, which decreases peroxide formation. It has also been shown that 4 Hz EMF-treated physiological solution modulates the growth and development of microbes and heart muscle contractility, but 8 Hz EMF has pronounced inhibitory effect on bacterial growth and development. Therefore, in order to elucidate the possible mechanism of 4 Hz and 8 Hz EMF effects on heart muscle function, in the present work the effects of 4 Hz and 8 Hz EMF exposures on heart muscle tissue hydration, the sensitivity of 4 Hz and 8 Hz EMF-induced tissue hydration to 10−4 M ouabain (Na+/K+ pump inhibition) and 10−9 M ouabain (activation of intracellular signaling system) as well as the effects of 4 Hz and 8 Hz EMF exposures on the number of Na+/K+ pump units in the membrane of both young and old rats have been studied. The obtained data allow us to suggest that 8 Hz EMF exposure has more pronounced age-dependent modulation effect on tissue hydration of heart muscle than 4 Hz EMF and this effect is sensitive to Na+/K+ pump activity and intracellular signaling system.展开更多
基金Supported by Grant-in-Aid from the Heart and Stroke Foundation of Ontario and a Doctoral Award to MMS from the Heartand Stroke Foundation of CanadaThis work is part of a pendingpatent and US Patent 7091174B2
文摘Plasma membrane Ca2+pumps(PMCA)play a major role in Ca2+homeostasis and signaling by extruding cellular Ca2+with high affinity.PMCA isoforms are encoded by four genes which are expressed differentially in various cell types in normal and disease states.Therefore, PMCA isoform selective inhibitors would aid in delineating their role in physiology and pathophysiology.We are testing the hypothesis that extracellular domains of PMCA can be used as allosteric targets to obtain a novel class of PMCA-specific inhibitors termed caloxins. This review presents the concepts behind the invention of caloxins and our progress in this area.A section is also devoted to the applications of caloxins in literature. We anticipate that isoform-selective caloxins will aid in understanding PMCA physiology in health and disease. With strategies to develop therapeutics from bioactive peptides,caloxins may become clinically useful in car diovascular diseases,neurological disorders,retinopathy,cancer and contraception.
基金Supported by A New Investigator Award from the BBSRC
文摘The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic metabolism,has the capacity to cause ATP depletion and thus inhibit PMCA activity.This has potentially fatal consequences,particularly for non-excitable cells in which the PMCA is the major Ca2+efflux pathway.This is because inhibition of the PMCA inevitably leads to cytosolic Ca2+ overload and the consequent cell death.However,the relationship between metabolic stress,ATP depletion and inhibition of the PMCA is not as simple as one would have originally predicted.There is increasing evidence that metabolic stress can lead to the inhibition of PMCA activity independent of ATP or prior to substantial ATP depletion.In particular,there is evidence that the PMCA has its own glycolytic ATP supply that can fuel the PMCA in the face of impaired mitochondrial function.Moreover, membrane phospholipids,mitochondrial membrane potential,caspase/calpain cleavage and oxidative stress have all been implicated in metabolic stress-induced inhibition of the PMCA.The major focus of this review is to challenge the conventional view of ATP-dependent regulation of the PMCA and bring together some of the alternative or additional mechanisms by which metabolic stress impairs PMCA activity resulting in cytosolic Ca2+ overload and cytotoxicity.
基金supported by the National Natural Science Foundation of China,No.81171239
文摘The regulatory mechanisms of cytoplasmic Ca2＋ after myocardial infarction-induced Ca2＋ overload involve secretory pathway Ca2＋-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi apparatus on Ca2＋ overload after cerebral ischemia and reperfusion remains unclear. Four-vessel occlusion rats were used as animal models of cerebral ischemia. The expression of secretory pathway Ca2＋-ATPase 1 in the cortex and hippocampus was detected by immunoblotting, and Ca2＋ concentrations in the cytoplasm and Golgi vesicles were determined. Results showed an overload of cytoplasmic Ca2＋ during ischemia and reperfusion that reached a peak after reperfusion. Levels of Golgi Ca2＋ showed an opposite effect. The expression of Golgi-specific secretory pathway Ca2＋-ATPase 1 in the cortex and hippocampus decreased before ischemia and reperfusion, and increased after reperfusion for 6 hours. This variation was similar to the alteration of calcium in separated Golgi vesicles. These results indicate that the Golgi apparatus participates in the formation and alleviation of calcium overload, and that secretory pathway Ca2＋-ATPase 1 tightly responds to ischemia and reperfusion in nerve cells. Thus, we concluded that secretory pathway Ca2＋-ATPase 1 plays an essential role in cytosolic calcium regulation and its expression can be used as a marker of Golgi stress, responding to cerebral ischemia and reperfusion. The secretory pathway Ca2＋-ATPase 1 can be an important neuroprotective target of ischemic stroke.
文摘In order to study the pathogenesis of hypertension associated with noninsulin dependent diabetes mellitus (NIDDM), Plasma glucose, insulin levels at fasting and following an oral glucose load were measured. Na +K +pump and Ca 2+ pump activities of red blood cell membrane were also assessed. Hypertensive patients with normal or impaired glucose tolerance (NGT, or IGT) had hyperinsulinemia. Obese hypertensive patients also had hyperinsulinemia, while nonobese hypertensive patients had no hyperinsulinemia, but exhibited a delay in insulin response to oral glucose tolerance test (OGTT). In multivariate analysis, considering the factors of age, BMI and plasma glucose level, DBP were still positively related to both 30 min insulin level and IAUC, but negatively correlated to activities of Na +K +pump and Ca 2+ pump. These results demonstrated that a link between obesity, hpertension and NIDDM is the insulin resistance and/or hyperinsulinemia.
文摘Previously we have shown that 4 Hz and 8 Hz EMF exposures have depressing effect on the thermodynamic activity of water, which decreases peroxide formation. It has also been shown that 4 Hz EMF-treated physiological solution modulates the growth and development of microbes and heart muscle contractility, but 8 Hz EMF has pronounced inhibitory effect on bacterial growth and development. Therefore, in order to elucidate the possible mechanism of 4 Hz and 8 Hz EMF effects on heart muscle function, in the present work the effects of 4 Hz and 8 Hz EMF exposures on heart muscle tissue hydration, the sensitivity of 4 Hz and 8 Hz EMF-induced tissue hydration to 10−4 M ouabain (Na+/K+ pump inhibition) and 10−9 M ouabain (activation of intracellular signaling system) as well as the effects of 4 Hz and 8 Hz EMF exposures on the number of Na+/K+ pump units in the membrane of both young and old rats have been studied. The obtained data allow us to suggest that 8 Hz EMF exposure has more pronounced age-dependent modulation effect on tissue hydration of heart muscle than 4 Hz EMF and this effect is sensitive to Na+/K+ pump activity and intracellular signaling system.
