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 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 apparat...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
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 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.
