MOLECULAR DETERMINANTS OF VOLTAGE-DEPENDENT INACTIVATION IN CALCIUM CHANNELS

VOLTAGE-DEPENDENT Ca2+ channels respond to membrane depolarization by conformational changes that control channel opening and eventual closi ng by inactivation(1-3). The kinetics of inactivation differ considera bly between types of Ca2+ channels(1-8) and are important in determini ng the amount of Ca2+ entry during electrical activity and its resulti ng impact on diverse cellular events(3). The most intensively characte rized forms of inactivation in potassium(9,10) and sodium channels(11- 13) involve pore block by a tethered plug(14). In contrast, little is known about the molecular basis of Ca2+-channel inactivation. We studi ed the molecular mechanism of inactivation of voltage-gated calcium ch annels by making chimaeras from channels with different inactivation r ates. We report here that the amino acids responsible for the kinetic differences are localized to membrane-spanning segment S6 of the first repeat of the alpha(1) subunit (IS6), and to putative extracellular a nd cytoplasmic domains flanking IS6. Involvement of this region in Ca2 +-channel inactivation was unexpected and raises interesting compariso ns with Na+ channels, where the III-IV loop is a critical structural d eterminant. Ca2+-channel inactivation has some features that resemble C-type inactivation of potassium channels.