Inactivation of Neuronal Calcium Channels

NATURE REVIEWS | NEUROSCIENCE VOLUME 3 | NOVEMBER 2002 | 873 Voltage-gated Ca channels (VGCCs) are a large family of integral membrane proteins that control the selective flow of Ca ions down their electrochemical gradient in response to changes in membrane potential (BOX 1; TABLE 1). Ca ions control processes as diverse as cell proliferation, neuronal development and transmitter release. All of these functions have to be accomplished within a narrow range of Ca concentrations, as this cation can be toxic if its level is not tightly controlled. So, effective mechanisms, such as pumps and exchangers, remove Ca ions from the cytoplasm, restoring the resting concentration once these ions have fulfilled their signalling role. But in addition to these pumps and exchangers, several mechanisms of channel inactivation have appeared during evolution to control Ca entry in the face of ongoing electrical activity. So, Ca channels can inactivate by three different mechanisms: Cadependent inactivation (CDI), fast voltage-dependent inactivation (VDI) and slow VDI. In the case of CDI, Ca ions restrict their own entry into the cell by one of the main routes of Ca influx, the VGCCs (FIG. 1a). This CDI provides crucial negative feedback in numerous neuronal and non-neuronal settings. The mechanisms that underlie this feedback inhibition have been under investigation for more than 20 years, but it was only recently that calmodulin (CaM) was identified as an important Ca sensor that mediates CDI. Here, we review the various mechanisms that have been proposed to mediate CDI, including the involvement of the cytoskeleton, the role of phosphorylation–dephosphorylation processes, and the participation of Ca-binding proteins. We then summarize the functional significance of CDI. We conclude by proposing an integrative model of this phenomenon, and suggest some future approaches to the study of CDI. For a detailed discussion of the mechanisms that underlie VDI (BOX 2), we refer the interested reader to REFS 10,11.