Mode-actions of the Na +-Ca 2+ exchanger: from genes to mechanisms to a new strategy in brain disorders

Abstract

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.