A new type of Ca 2+ channel blocker that targets Ca 2+ sensors and prevents Ca 2+ ‐mediated apoptosis

Calmodulin (CaM), as well as other Ca 2+ binding motifs (i.e., EF hands), have been demonstrated to be Ca 2+ sensors for several ion channel types, usually resulting in an inactivation in a negative feedback manner. This provides a novel target for the regulation of such channels. We have designed peptides that interact with EF hands of CaM in a specific and productive manner. Here we have examined whether these peptides block certain Ca 2+ ‐permeant channels and inhibit biological activity that is dependent on the influx of Ca 2+ . We found that these peptides are able to enter the cell and directly, as well as indirectly (through CaM), block the activity of glutamate receptor channels in cultured neocortical neurons and a nonselective cation channel in Jurkat T cells that is activated by HIV‐1 gp120. As a consequence, apoptosis mediated by an influx of Ca 2+ through these channels was also dose‐dependently inhibited by these novel peptides. Thus, this new type of Ca 2+ channel blocker may have utility in controlling apoptosis due to HIV infection or neuronal loss due to ischemia.—Manion, M. K., Su, Z., Villain, M., Blalock, J. E. A new type of Ca 2+ channel blocker that targets Ca 2+ sensors and prevents Ca 2+ ‐mediated apoptosis. FASEB J. 14, 1297–1306 (2000)