Calmodulation of Voltage-Gated Calcium Channels: Frontiers of Biological Impact and Mechanistic Elegance

Abstract

Calmodulin (CaM) regulation of mammalian CaV channels is both biologically critical and mechanistically rich, rendering this system a central prototype for the decoding of Ca2+ signals and the modulation of channels. This system showcases the remarkable ability of the N- and C-terminal lobes of CaM to function as semiautonomous Ca2+ sensors and effectors, a theme initially recognized in Paramecium (Cell 62:165). In mammalian CaV channels, Ca2+-free CaM (apoCaM) starts off already preassociated with a host channel, and then the C-lobe turns out to respond preferentially to the strong Ca2+ influx through the host channel to induce one form of channel modulation (local selectivity), whereas the N-lobe frequently prefers the far weaker Ca2+ signal emanating from Ca2+ sources at a distance (global selectivity). These striking contrasts in spatial Ca2+ selectivity, crucial to biological Ca2+ signaling, can be simply explained by mechanisms involving the translocation of CaM among an apoCaM preassociation locus and multiple Ca2+/CaM effector sites (Cell 133:1228). However, beyond apoCaM preassociation at an IQ domain on the carboxy-terminus of channels, little has been definitively established regarding the structural identity of Ca2+/CaM effector sites, outside of an NSCaTE element in the channel amino terminus (Nature 451:830). Here, we outline new evidence identifying dominant Ca2+/CaM effector sites outside of the IQ and NSCaTE regions (Ben Johnny et al, Bazzazi et al, this meeting), thereby bolstering a modulatory mechanism wherein CaM departs from an initial IQ preassociation locus, then interacts with structurally distinct effector sites. This intricate translocating dance of CaM complexed with a target molecule may be a general scheme enabling high-order Ca2+ decoding in many signaling complexes throughout biology; indeed, an analogous hypothesis of migratory CaM has been proposed for NaV channels (J. Biol. Chem. 284:6436).