Conversion of an inactive cardiac dihydropyridine receptor II-III loop segment into forms that activate skeletal ryanodine receptors

A 25 amino acid segment (Glu(666)-Pro(691)) of the II-III loop of the alpha (1) subunit of the skeletal dihydropyridine receptor, but not the correspon ding cardiac segment (Asp(788)-Pro(814)), activates skeletal ryanodine rece ptors, To identify the structural domains responsible for activation of ske letal ryanodine receptors, we systematically replaced amino acids of the ca rdiac II-III loop with their skeletal counterparts. ri cluster of five basi c residues of the skeletal II-III loop ((RKRRK685)-R-681) was indispensable for activation of skeletal ryanodine receptors, In the cardiac segment, a negatively charged residue (Glu(804)) appears to diminish the electrostatic potential created by this basic cluster. In addition, Glu(800) in the grou p of negatively charged residues (EEEEE802)-E-798 of the cardiac II-III loo p may serve to prevent the binding of the activation domain. (C) 1999 Feder ation of European Biochemical Societies.