Essential Ca²⁺-binding motif for Ca²⁺-sensitive inactivation of L-type Ca²⁺ channels

Intracellular calcium (Ca²⁺) inhibits the opening of L-type (α_1C) 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 Ca²⁺ channels derived from parental α_1C and α_1E channels, the latter of which is a neuronal channel lacking Ca²⁺ inactivation. A consensus Ca²⁺-binding motif (an EF hand), located on the α_1C subunit, was required for Ca²⁺ inactivation. Donation of the α_1C EF-hand region to the α_1E channel conferred the Ca²⁺-inactivating phenotype. These results strongly suggest that Ca²⁺ binding to the α_1C subunit initiates Ca²⁺ inactivation.