Repeat I of the dihydropyridine receptor is critical in determining calcium channel activation kinetics

Abstract

MEMBRANE depolarization causes many kinds of ion channels to open, a process termed activation¹. For both Na⁺ channels^2–4 and Ca²⁺ channels^5,6, kinetic analysis of current has suggested that during activation the channel undergoes several conformational changes before reaching the open state. Structurally, these channels share a common motif⁷: the central element is a large polypeptide with four repeating units of homology (repeats I-IV), each containing a voltage-sensing region, the S4 segment^8–11. This suggests that the distinct conformational transitions inferred from kinetic analysis may be equated with conformational changes of the individual structural repeats⁸. To investigate the molecular basis of channel activation, we constructed complementary DNAs encoding chimaeric Ca²⁺ channels in which one or more of the four repeats of the skeletal muscle dihydropyridine receptor are replaced by the corresponding repeats derived from the cardiac dihydropyridine receptor. We report here that repeat I determines whether the chimaeric Ca²⁺ channel shows slow (skeletal muscle-like) ¹² or rapid (cardiac-like) ¹³ activation.