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A new type of Ca²⁺ channel blocker that targets Ca²⁺ sensors and prevents Ca²⁺-mediated apoptosis

University of Alabama at Birmingham, Department of Physiology and Biophysics, Birmingham, Alabama 35294, USA

²Correspondence: University of Alabama at Birmingham, Department of Physiology and Biophysics, McCallum Building, Rm. 898, 1918 University Blvd., Birmingham, Alabama 35294, USA. E-mail: blalock{at}uab.edu

Calmodulin (CaM), as well as other Ca²⁺ binding motifs (i.e., EF hands), have been demonstrated to be Ca²⁺ 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 Ca²⁺-permeant channels and inhibit biological activity that is dependent on the influx of Ca²⁺. 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 Ca²⁺ through these channels was also dose-dependently inhibited by these novel peptides. Thus, this new type of Ca²⁺ 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 Ca²⁺ channel blocker that targets Ca²⁺ sensors and prevents Ca²⁺-mediated apoptosis.

Key Words: calmodulin • CALP • Fura-2 • cation channel • complementary peptide • antisense peptide

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