Mechanism of Local and Global Ca²⁺ Sensing by Calmodulin in Complex with a Ca²⁺ Channel

Calmodulin (CaM) in complex with Ca²⁺ channels constitutes a prototype for Ca²⁺ sensors that are intimately colocalized with Ca²⁺ sources. The C-lobe of CaM senses local, large Ca²⁺ oscillations due to Ca²⁺ influx from the host channel, and the N-lobe senses global, albeit diminutive Ca²⁺ changes arising from distant sources. Though biologically essential, the mechanism underlying global Ca²⁺ sensing has remained unknown. Here, we advance a theory of how global selectivity arises, and we experimentally validate this proposal with methodologies enabling millisecond control of Ca²⁺ oscillations seen by the CaM/channel complex. We find that global selectivity arises from rapid Ca²⁺ release from CaM combined with greater affinity of the channel for Ca²⁺-free versus Ca²⁺-bound CaM. The emergence of complex decoding properties from the juxtaposition of common elements, and the techniques developed herein, promise generalization to numerous molecules residing near Ca²⁺ sources.