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, Ca2+-efflux via an active mode of the Na+-Ca2+ exchanger was elicited by hydrogen peroxide (H2O2) after preincubation of the cell with a Ca2+-free medium, whereas Ca2+-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 [Ca-45(2+)] uptake of transfected CHO cells at given time intervals or extracellular Na+[Na+](0) 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 intracellularly distributed tetra-cluster (named VISA(931)) 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 P-2-purinergic receptors, blocking Ca2+ influx and catalyzing the dismutation of superoxide anions (O-2(.)) to H2O2. In conclusion, knowledge-based drug design is a new strategy for developing promising candidates of neuroprotective agents. (C) 1998 Elsevier, Paris.