A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels

Ca2+/calmodulin-dependent regulation of voltage-gated CaV1–2 Ca2+ channels shows extraordinary modes of spatial Ca2+ decoding and channel modulation1,2,3,4,5,6, vital for many biological functions6,7,8,9. A single calmodulin (CaM) molecule associates constitutively with the channel’s carboxy-terminal tail3,10,11,12,13, and Ca2+ binding to the C-terminal and N-terminal lobes of CaM can each induce distinct channel regulations2,14. As expected from close channel proximity, the C-lobe responds to the roughly 100-μM Ca2+ pulses driven by the associated channel15,16, a behaviour defined as ‘local Ca2+ selectivity’. Conversely, all previous observations have indicated that the N-lobe somehow senses the far weaker signals from distant Ca2+ sources2,3,17,18. This ‘global Ca2+ selectivity’ satisfies a general signalling requirement, enabling a resident molecule to remotely sense cellular Ca2+ activity, which would otherwise be overshadowed by Ca2+ entry through the host channel5,6. Here we show that the spatial Ca2+ selectivity of N-lobe CaM regulation is not invariably global but can be switched by a novel Ca2+/CaM-binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial Ca2+ transforming element). Native CaV2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial Ca2+ selectivity transforms from a global to local profile. Given this effect, we examined CaV1.2/CaV1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, differences in spatial selectivity between advanced CaV1 and CaV2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel’s amino terminus indicates that CaM can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global Ca2+ selectivity19.