Intracellular calcium (Ca2+) inhibits the opening of L-type (alpha(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 pare
ntal alpha(1C) and alpha(1E) channels, the latter of which is a neuron
al channel lacking Ca2+ inactivation. A consensus Ca2+-binding motif (
an EF hand), located on the alpha(1C) subunit, was required for Ca2+ i
nactivation. Donation of the alpha(1C) EF-hand region to the alpha(1E)
channel conferred the Ca2+-inactivating phenotype. These results stro
ngly suggest that Ca2+ binding to the alpha(1C) subunit initiates Ca2 inactivation.