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.