Mode-actions of the Na(+)-Ca2+ exchanger: from genes to mechanisms to a new strategy in brain disorders.
Mode-actions of the Na(+)-Ca2+ exchanger from genes to mechanisms to a new strategy for brain disorders were comparatively studied in oxidative stress. In transfected Chinese hamster ovary (CHO) cells steadily expressing the Na(+)-Ca2+ exchanger's gene, Ca(2+)-efflux via an active mode of the Na(+)-Ca2+ exchanger was elicited by hydrogen peroxide (H2O2) after preincubation of the cell with a Ca(2+)-free medium, whereas Ca(2+)-influx via a reverse mode of the Na(+)-Ca2+ exchanger was dramatically evoked by H2O2 after preincubation of the cell with a Ca2+ medium, as a prelude to neuronal death. According to [45Ca2+] uptake of transfected CHO cells at given time intervals or extracellular Na+[Na+]o gradients, hyperbola, logarithmic and sigmoid curve equations of the Na(+)-Ca2+ exchanger's mode-actions were respectively defined in the absence and the presence of H2O2. The Na(+)-Ca2+ exchanger's conformational transition in oxidative stress was dominated by adenosine triphosphate (ATP)-dependent cytoskeletal redox modification, cation-pi interactions and secondary Ca2+ activation. These mechanisms were used to generate an intracellulary distributed tetra-cluster (named VISA931) for rescuing G-protein agonist-sensitive signal transduction and cortico-cerebral somatosensory evoke potential (SEP) from oxidation via activating forward operation of the Na(+)-Ca2+ exchanger, the beta-adrenergic and the P2-purinergic receptors, blocking Ca2+ influx and catalyzing the dismutation of superoxide anions (O2-.) to H2O2. In conclusion, knowledge-based drug design is a new strategy for developing promising candidates of neuroprotective agents.
Department of Anesthesiology, Zhong Shan Hospital, Shanghai Medical University, China.
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D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000502:physiology; D006224:Cricetinae; D004285:Dogs; D004578:Electron Spin Resonance Spectroscopy; D005073:Evoked Potentials, Somatosensory / Q000502:physiology*; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D009129:Muscle Tonus; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D017607:Aluminum Compounds; D011994:Recombinant Proteins; D019831:Sodium-Calcium Exchanger; D013481:Superoxides; C050992:tetrafluoroaluminate; D019204:GTP-Binding Proteins; D005459:Fluorides; D002118:Calcium