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Letters to Nature
Nature 352, 800 - 803 (29 August 1991); doi:10.1038/352800a0

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

Tsutomu Tanabe*, Brett A. Adams, Shosaku Numa* & Kurt G. Beam

*Departments of Medical Chemistry and Molecular Genetics, Kyoto University Faculty of Medicine, Kyoto 606, Japan
Department of Physiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA
To whom correspondence should be addressed

MEMBRANE depolarization causes many kinds of ion channels to open, a process termed activation1. For both Na+ channels2–4 and Ca2+ channels5,6, 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 segment8–11. 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.

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