Intracellular calcium (Ca2+) inhibits the opening of L-type (α1C) Ca2+ channels, providing physiological control of Ca2+ entry into a wide variety of cells. A structural determinant of this Ca2+-sensitive inactivation was revealed by chimeric Ca 2+ channels derived from parental α1C and α1E channels, the latter of which is a neuronal channel lacking Ca2+ inactivation. A consensus Ca2+-binding motif (an EF hand), located on the α1C subunit, was required for Ca 2+ inactivation. Donation of the α1C EF-hand region to the α1E channel conferred the Ca2+-inactivating phenotype. These results strongly suggest that Ca2+ binding to the α1C subunit initiates Ca2+ inactivation.
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