MODE-ACTIONS OF THE NA-CA2+ EXCHANGER - FROM GENES TO MECHANISMS TO ANEW STRATEGY IN BRAIN DISORDERS()

Mode-actions of the Na+-Ca2+ exchanger from genes to mechanisms to a n ew strategy for brain disorders were comparatively studied in oxidativ e stress. In transfected Chinese hamster ovary (CHO) cells steadily ex pressing the Na+-Ca2+ exchanger's gene, Ca2+-efflux via an active mode of the Na+-Ca2+ exchanger was elicited by hydrogen peroxide (H2O2) af ter preincubation of the cell with a Ca2+-free medium, whereas Ca2+-in flux via a reverse mode of the Na+-Ca2+ exchanger was dramatically evo ked by H2O2 after preincubation of the cell with a Ca2+ medium, as a p relude to neuronal death. According to [Ca-45(2+)] uptake of transfect ed CHO cells at given time intervals or extracellular Na+[Na+](0) grad ients, hyperbola, logarithmic and sigmoid curve equations of the Na+-C a2+ exchanger's mode-actions were respectively defined in the absence and the presence of H2O2. The Na+-Ca2+ exchanger's conformational tran sition in oxidative stress was dominated by adenosine triphosphate (AT P)-dependent cytoskeletal redox modification, cation-pi interactions a nd secondary Ca2+ activation. These mechanisms were used to generate a n intracellularly distributed tetra-cluster (named VISA(931)) for resc uing G-protein agonist-sensitive signal transduction and cortico-cereb ral somatosensory evoke potential (SEP) from oxidation via activating forward operation of the Na+-Ca2+ exchanger, the beta-adrenergic and t he P-2-purinergic receptors, blocking Ca2+ influx and catalyzing the d ismutation of superoxide anions (O-2(.)) to H2O2. In conclusion, knowl edge-based drug design is a new strategy for developing promising cand idates of neuroprotective agents. (C) 1998 Elsevier, Paris.