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

Abstract

A 25 amino acid segment (Glu 666–Pro 691) of the II-III loop of the α 1 subunit of the skeletal dihydropyridine receptor, but not the corresponding cardiac segment (Asp 788–Pro 814), activates skeletal ryanodine receptors. To identify the structural domains responsible for activation of skeletal ryanodine receptors, we systematically replaced amino acids of the cardiac II-III loop with their skeletal counterparts. A cluster of five basic residues of the skeletal II-III loop ( 681RKRRK 685) 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 group of negatively charged residues 798EEEEE 802 of the cardiac II-III loop may serve to prevent the binding of the activation domain.