Novel Modulatory Action of Calmodulin Complexation with L-Type Channels

Abstract

L-type Ca2+ channels convey vital Ca2+ inflow, which is critically down-regulated by intracellular Ca2+. This Ca2+-dependent inactivation (CDI) is only present in channels initially preassociated with Ca2+-free calmodulin (apoCaM), where subsequent Ca2+ binding to this ‘resident' calmodulin (CaM) inactivates channels (Nature463:968). Channels lacking preassociated apoCaM fail to undergo CDI. Canonical L-type channels bind apoCaM so avidly that nearly all channels are ‘charged' with apoCaM. However, natural variants feature potentially lower apoCaM affinity, so fluctuations in ambient apoCaM may tune overall CDI. Here, we demonstrate that channel preassociation with apoCaM does more than simply enable CDI, and strikingly enhances open probability (PO). For example, in single-channel Ba2+ currents (to avoid CDI), taken from a variant with low apoCaM affinity, openings are sparse under baseline apoCaM (a, left), but prolific upon apoCaM overexpression (a, right). Corresponding PO-V relations confirm this effect of apoCaM (b). Importantly, the baseline PO of differing channel variants increases with channel/apoCaM affinity via a Langmuir function (c). Thus, PO variability reflects differences in apoCaM preassociation, not contrasts in channel composition per se. These results suggest that ambient apoCaM levels can tune both CDI and PO of channels.