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

Ca2+/ calmodulin- dependent regulation of voltage- gated Ca(V)1 - 2 Ca2+ channels shows extraordinary modes of spatial Ca2+ decoding and channel modulation(1-6), vital for many biological functions(6-9). A single calmodulin ( CaM) molecule associates constitutively with the channel's carboxy- terminal tail(3,10-13), and Ca2+ binding to the C- terminal and N- terminal lobes of CaM can each induce distinct channel regulations(2,14). As expected from close channel proximity, the C- lobe responds to the roughly 100-mu M Ca2+ pulses driven by the associated channel(15,16), 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+ sources(2,3,17,18). 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 channel(5,6). 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 Ca(V)2.2 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 Ca(V)1.2/ Ca(V)1.3 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 Ca(V)1 and Ca(V)2 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+ selectivity(19).