A new type of Ca channel blocker that targets Ca sensors and prevents Ca-mediated apoptosis

Calmodulin (CaM), as well as other Ca binding motifs (i.e., EF hands), have been demonstrated to be Ca 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-permeant channels and inhibit biological activity that is dependent on the influx of Ca. 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 through these channels was also dose-dependently inhibited by these novel peptides. Thus, this new type of Ca 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 channel blocker that targets Ca sensors and prevents Ca-mediated apoptosis. FASEB J. 14, 1297–1306 (2000)