Calcium-dependent inactivation of neuronal calcium channels

Calcium channels can be inactivated through three different mechanisms: fast and slow voltage-dependent inactivation, and Ca2+-dependent inactivation (CDI). Different Ca2+ channels show different types of inactivation; CDI is characteristic of L-type Ca2+ channels, which have been the focus of most studies of this phenomenon. There are several hallmarks of CDI. First, CDI tends to be fast. Second, CDI normally results in a U-shaped inactivation curve. Third, the use of Ba2+ as the principal charge carrier affects the kinetics of inactivation. Fourth, CDI can be retarded by increasing the Ca2+-buffering capacity of the cytoplasm through the introduction of exogenous buffers. Last, single-channel recordings reveal smaller current amplitudes during CDI, and the unitary channel opens less frequently, with rare openings after several minutes. Different mechanisms have been put forward to account for CDI. They include a potential contribution of Ca2+-induced Ca2+ release from the endoplasmic reticulum and the direct binding of Ca2+ to the channel. However, recent studies have highlighted a prominent role of phosphorylation and of calmodulin binding to the channel. Last, the cytoskeleton has also been shown to exert a modulatory influence on CDI. The functional significance of CDI is not fully understood, although it seems likely that it participates in the activity-dependent regulation of transmitter release. In addition to understanding the function of this inactivation mechanism, the main challenge for future work will be to determine the nature of the transduction mechanism that couples Ca2+ binding to channel closure, and to localize protein assemblies that are relevant for CDI in specific functional cellular compartments.