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J Mol Biol. 2013 Sep 9;425(17):3217-34. doi: 10.1016/j.jmb.2013.06.024. Epub 2013 Jun 25.

Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain.

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Cardiovascular Research Institute, University of California, San Francisco, CA 94158-9001, USA.


In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation and limits calcium entry, whereas CaBP1 blocks calcium-dependent inactivation (CDI) and allows sustained calcium influx. Here, we combine isothermal titration calorimetry with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca(2+)/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium-binding properties. The observation that the apo forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity.


C-lobe; C-terminal lobe; CDI; CaBP1; CaM; ITC; N-lobe; N-terminal lobe; calcium sensor proteins; calcium-binding protein 1; calcium-dependent inactivation; calmodulin; electrophysiology; isothermal titration calorimetry; mathematical models; voltage-gated calcium channel

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