Mechanism of local and global Ca2+ sensing by calmodulin in complex with a Ca2+ channel.
Calmodulin (CaM) in complex with Ca(2+) channels constitutes a prototype for Ca(2+) sensors that are intimately colocalized with Ca(2+) sources. The C-lobe of CaM senses local, large Ca(2+) oscillations due to Ca(2+) influx from the host channel, and the N-lobe senses global, albeit diminutive Ca(2+) changes arising from distant sources. Though biologically essential, the mechanism underlying global Ca(2+) 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 Ca(2+) oscillations seen by the CaM/channel complex. We find that global selectivity arises from rapid Ca(2+) release from CaM combined with greater affinity of the channel for Ca(2+)-free versus Ca(2+)-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 Ca(2+) sources.
Tadross
Michael R
MR
Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Dick
Ivy E
IE
Yue
David T
DT
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D016296:Mutagenesis; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D051381:Rats
C503279:Cacna1b protein, rat; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D002147:Calmodulin; C093712:Cacna1d protein, rat; D002118:Calcium