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

This article has been updated


Ca2+/calmodulin-dependent regulation of voltage-gated CaV1–2 Ca2+ channels shows extraordinary modes of spatial Ca2+ decoding and channel modulation1,2,3,4,5,6, vital for many biological functions6,7,8,9. A single calmodulin (CaM) molecule associates constitutively with the channel’s carboxy-terminal tail3,10,11,12,13, and Ca2+ binding to the C-terminal and N-terminal lobes of CaM can each induce distinct channel regulations2,14. As expected from close channel proximity, the C-lobe responds to the roughly 100-μM Ca2+ pulses driven by the associated channel15,16, 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+ sources2,3,17,18. 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 channel5,6. 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 CaV2.2 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 CaV1.2/CaV1.3 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 CaV1 and CaV2 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+ selectivity19.

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Figure 1: Transformation of spatial Ca 2+ selectivity in Ca V 2.2 channels.
Figure 2: Direct CaM binding and mapping of key NSCaTE residues.
Figure 3: NSCaTE transforms spatial Ca 2+ selectivity in native Ca V 1 channels.
Figure 4: Functional and structural properties for NSCaTE switching of spatial Ca 2+ selectivity.

Change history

  • 14 February 2008

    In the AOP version of this paper the nomenclature for N and C termini was confusing. The use of 'N and C termini' should always refer to calmodulin (CaM) and 'amino and carboxy termini' should refer to the channel. These changes were made on 14 February 2008, and the print version is correct.


  1. 1

    Lee, A., Scheuer, T. & Catterall, W. A. Ca2+/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channels. J. Neurosci. 20, 6830–6838 (2000)

    CAS  Article  Google Scholar 

  2. 2

    DeMaria, C. D., Soong, T. W., Alseikhan, B. A., Alvania, R. S. & Yue, D. T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels. Nature 411, 484–489 (2001)

    CAS  ADS  Article  Google Scholar 

  3. 3

    Liang, H. et al. Unified mechanisms of Ca2+ regulation across the Ca2+ channel family. Neuron 39, 951–960 (2003)

    CAS  Article  Google Scholar 

  4. 4

    Bootman, M. D., Lipp, P. & Berridge, M. J. The organisation and functions of local Ca2+ signals. J. Cell Sci. 114, 2213–2222 (2001)

    CAS  PubMed  Google Scholar 

  5. 5

    Evans, R. M. & Zamponi, G. W. Presynaptic Ca2+ channels—integration centers for neuronal signaling pathways. Trends Neurosci. 29, 617–624 (2006)

    CAS  Article  Google Scholar 

  6. 6

    Dunlap, K. Calcium channels are models of self-control. J. Gen. Physiol. 129, 379–383 (2007)

    CAS  Article  Google Scholar 

  7. 7

    Alseikhan, B. A., DeMaria, C. D., Colecraft, H. M. & Yue, D. T. Engineered calmodulins reveal the unexpected eminence of Ca2+ channel inactivation in controlling heart excitation. Proc. Natl Acad. Sci. USA 99, 17185–17190 (2002)

    CAS  ADS  Article  Google Scholar 

  8. 8

    Xu, J. & Wu, L. G. The decrease in the presynaptic calcium current is a major cause of short-term depression at a calyx-type synapse. Neuron 46, 633–645 (2005)

    CAS  Article  Google Scholar 

  9. 9

    Dolmetsch, R. E., Pajvani, U., Fife, K., Spotts, J. M. & Greenberg, M. E. Signaling to the nucleus by an L-type calcium channel–calmodulin complex through the MAP kinase pathway. Science 294, 333–339 (2001)

    CAS  ADS  Article  Google Scholar 

  10. 10

    Mori, M. X., Erickson, M. G. & Yue, D. T. Functional stoichiometry and local enrichment of calmodulin interacting with Ca2+ channels. Science 304, 432–435 (2004)

    CAS  ADS  Article  Google Scholar 

  11. 11

    Yang, P. S., Mori, M. X., Antony, E. A., Tadross, M. R. & Yue, D. T. A single calmodulin imparts distinct N- and C-lobe regulatory processes to individual CaV1.3 channels. Biophys. J. Suppl. 354a, 1669-Plat (2007)

  12. 12

    Pitt, G. S. et al. Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of L-type Ca2+ channels. J. Biol. Chem. 276, 30794–30802 (2001)

    CAS  Article  Google Scholar 

  13. 13

    Erickson, M. G., Liang, H., Mori, M. X. & Yue, D. T. FRET two-hybrid mapping reveals function and location of L-type Ca2+ channel CaM preassociation. Neuron 39, 97–107 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Yang, P. S. et al. Switching of Ca2+-dependent inactivation of Cav1.3 channels by calcium binding proteins of auditory hair cells. J. Neurosci. 26, 10677–10689 (2006)

    CAS  Article  Google Scholar 

  15. 15

    Augustine, G. J., Santamaria, F. & Tanaka, K. Local calcium signaling in neurons. Neuron 40, 331–346 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Neher, E. Vesicle pools and Ca2+ microdomains: new tools for understanding their roles in neurotransmitter release. Neuron 20, 389–399 (1998)

    CAS  Article  Google Scholar 

  17. 17

    Chaudhuri, D., Issa, J. B. & Yue, D. T. Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels. J. Gen. Physiol. 129, 385–401 (2007)

    CAS  Article  Google Scholar 

  18. 18

    Song, L. S., Sham, J. S., Stern, M. D., Lakatta, E. G. & Cheng, H. Direct measurement of SR release flux by tracking ‘Ca2+ spikes’ in rat cardiac myocytes. J. Physiol. (Lond.) 512, 677–691 (1998)

    CAS  Article  Google Scholar 

  19. 19

    Tadross, M. R., Dick, I. E. & Yue, D. T. Mechanism of Ca2+ decoding by the CaM/CaV channel complex. Biophys. J. Suppl. 354a, 1670-Plat (2007)

  20. 20

    Peterson, B. Z., DeMaria, C. D., Adelman, J. P. & Yue, D. T. Calmodulin is the Ca2+ sensor for Ca2+-dependent inactivation of L-type calcium channels. Neuron 22, 549–558 (1999)

    CAS  Article  Google Scholar 

  21. 21

    Tang, Z. Z. et al. Transcript scanning reveals novel and extensive splice variations in human l-type voltage-gated calcium channel, Cav1.2α1 subunit. J. Biol. Chem. 279, 44335–44343 (2004)

    CAS  Article  Google Scholar 

  22. 22

    Van Petegem, F., Chatelain, F. C. & Minor, D. L. Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain-Ca2+/calmodulin complex. Nature Struct. Mol. Biol. 12, 1108–1115 (2005)

    CAS  Article  Google Scholar 

  23. 23

    Ivanina, T., Blumenstein, Y., Shistik, E., Barzilai, R. & Dascal, N. Modulation of L-type Ca2+ channels by Gβγ and calmodulin via interactions with N and C termini of α1C . J. Biol. Chem. 275, 39846–39854 (2000)

    CAS  Article  Google Scholar 

  24. 24

    de Leon, M. et al. Essential Ca2+-binding motif for Ca2+-sensitive inactivation of L-type Ca2+ channels. Science 270, 1502–1506 (1995)

    CAS  ADS  Article  Google Scholar 

  25. 25

    Rhoads, A. R. & Friedberg, F. Sequence motifs for calmodulin recognition. FASEB J. 11, 331–340 (1997)

    CAS  Article  Google Scholar 

  26. 26

    Toescu, E. C. & Verkhratsky, A. The importance of being subtle: small changes in calcium homeostasis control cognitive decline in normal aging. Aging Cell 6, 267–273 (2007)

    CAS  Article  Google Scholar 

  27. 27

    Moosmang, S. et al. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. J. Neurosci. 25, 9883–9892 (2005)

    CAS  Article  Google Scholar 

  28. 28

    Evans, J., Erickson, M. G., Anderson, M. J. & Yue, D. T. FRET-based mapping of calmodulin preassociation with P/Q-type Ca channels. Biophys. J. Suppl. 84a, 2615-Pos (2003)

  29. 29

    Kobrinsky, E., Schwartz, E., Abernethy, D. R. & Soldatov, N. M. Voltage-gated mobility of the Ca2+ channel cytoplasmic tails and its regulatory role. J. Biol. Chem. 278, 5021–5028 (2003)

    CAS  Article  Google Scholar 

  30. 30

    Drum, C. L. et al. Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin. Nature 415, 396–402 (2002)

    CAS  ADS  Article  Google Scholar 

  31. 31

    Agler, H. L. et al. G protein-gated inhibitory module of N-type (CaV2.2) Ca2+ channels. Neuron 46, 891–904 (2005)

    CAS  Article  Google Scholar 

  32. 32

    Xu, W. & Lipscombe, D. Neuronal CaV1.3α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J. Neurosci. 21, 5944–5951 (2001)

    CAS  Article  Google Scholar 

  33. 33

    Williams, M. E. et al. Structure and functional expression of an omega-conotoxin- sensitive human N-type calcium channel. Science 257, 389–395 (1992)

    CAS  ADS  Article  Google Scholar 

  34. 34

    Wei, X. Y. et al. Heterologous regulation of the cardiac Ca2+ channel α1 subunit by skeletal muscle β and γ subunits. Implications for the structure of cardiac L-type Ca2+ channels. J. Biol. Chem. 266, 21943–21947 (1991)

    CAS  PubMed  Google Scholar 

  35. 35

    Perez-Reyes, E. et al. Cloning and expression of a cardiac/brain β subunit of the L- type calcium channel. J. Biol. Chem. 267, 1792–1797 (1992)

    CAS  PubMed  Google Scholar 

  36. 36

    Tomlinson, W. J. et al. Functional properties of a neuronal class C L-type calcium channel. Neuropharmacology 32, 1117–1126 (1993)

    CAS  Article  Google Scholar 

  37. 37

    Stratton, J., Evans, J., Erickson, M. G., Alvania, R. S. & Yue, D. T. The nature of concentration-dependent spurious FRET arising from CFP and YFP. Biophys. J. 86, 317a (2004)

    Google Scholar 

  38. 38

    Kincaid, R. L., Billingsley, M. L. & Vaughan, M. Preparation of fluorescent, cross-linking, and biotinylated calmodulin derivatives and their use in studies of calmodulin-activated phosphodiesterase and protein phosphatase. Methods Enzymol. 159, 605–626 (1988)

    CAS  Article  Google Scholar 

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We thank H. Agler and M. Mori for early characterization of the cBBBBb chimaeric channel; C. Iwema and J. Pevsner for bioinformatics advice; K.-W. Yau, E. Young and members of the Calcium Signals Laboratory for comments. Supported by grants from the NINDS (to I.E.D.), the NIGMS (to M.R.T.), and the NIMH and NHLBI (to D.T.Y.).

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Correspondence to David T. Yue.

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Supplementary Information

The file contains Supplementary Notes with Supplementary Figures S1-S11 and additional references. This file was replaced on 4 February 2008. (PDF 3282 kb)

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Dick, I., Tadross, M., Liang, H. et al. A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature 451, 830–834 (2008).

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