Structural determinants of fast inactivation of high voltage-activated Ca(2+) channels

The fast inactivation of voltage-dependent Ca(2+) channels is a key mechanism that contributes to the precise control of Ca(2+) entry into excitable cells. Recent advances have revealed that multiple structural elements contribute to the intrinsic inactivation properties of the alpha(1) subunit, including its cytoplasmic and transmembrane regions. Another major determinant of Ca(2+) channel inactivation is the association with one of four types of ancillary beta subunits that differentially modulate the intrinsic inactivation properties of the alpha(1) subunit. This could occur partly via interactions with the N-terminal region of the alpha(1) subunit and through lipid modification of the beta subunit. However, the latest findings suggest a mechanism in which fast Ca(2+) channel inactivation could occur through physical occlusion of the pore of the channel in a manner reminiscent of Na(+) and K(+) channel inactivation.