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Calcium-dependent inactivation of neuronal calcium channels

Nature Reviews Neuroscience volume 3, pages 873–883 (2002)Cite this article

Key Points

  • Calcium channels can be inactivated through three different mechanisms: fast and slow voltage-dependent inactivation, and Ca2+-dependent inactivation (CDI). Different Ca2+ channels show different types of inactivation; CDI is characteristic of L-type Ca2+ channels, which have been the focus of most studies of this phenomenon.

  • There are several hallmarks of CDI. First, CDI tends to be fast. Second, CDI normally results in a U-shaped inactivation curve. Third, the use of Ba2+ as the principal charge carrier affects the kinetics of inactivation. Fourth, CDI can be retarded by increasing the Ca2+-buffering capacity of the cytoplasm through the introduction of exogenous buffers. Last, single-channel recordings reveal smaller current amplitudes during CDI, and the unitary channel opens less frequently, with rare openings after several minutes.

  • Different mechanisms have been put forward to account for CDI. They include a potential contribution of Ca2+-induced Ca2+ release from the endoplasmic reticulum and the direct binding of Ca2+ to the channel. However, recent studies have highlighted a prominent role of phosphorylation and of calmodulin binding to the channel. Last, the cytoskeleton has also been shown to exert a modulatory influence on CDI.

  • The functional significance of CDI is not fully understood, although it seems likely that it participates in the activity-dependent regulation of transmitter release. In addition to understanding the function of this inactivation mechanism, the main challenge for future work will be to determine the nature of the transduction mechanism that couples Ca2+ binding to channel closure, and to localize protein assemblies that are relevant for CDI in specific functional cellular compartments.

Abstract

Calcium ions are ubiquitous intracellular mediators of numerous cellular processes. One of the main mechanisms of Ca2+ entry into the cell involves the opening of Ca2+ channels in the plasma membrane. To effectively control Ca2+ signalling, Ca2+ channels inactivate rapidly by a mechanism that depends on an elevation of intracellular Ca2+ within tens of nanometres of the channel pore. A structural understanding of this mechanism will provide a framework for understanding the regulation of Ca2+ entry and accumulation in neurons. Recent physiological, biochemical and molecular studies have yielded new insights into the regulation of neuronal Ca2+ channels.

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Figure 1: Electrophysiological hallmarks of the CDI of VGCCs.
Figure 2: Inactivation profile of VGCC subtypes in central neurons.
Figure 3: Regulation of L-type Ca2+ channels by Ca2+ and phosphorylation–dephosphorylation reactions.
Figure 5: Model of CDI and CDF induction by CaM in CaV2.1 Ca2+ channels.
Figure 4: Model of CDI induction by CaM in CaV1.2 Ca2+ channels.
Figure 6: Schematic overview of the main mechanisms leading to and influencing CDI in central neurons.

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References

  1. Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).An excellent paper that provides a review of all aspects of cellular Ca2+ signalling.

    CAS  Google Scholar 

  2. Catterall, W. A. Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24, 307–323 (1998).

    CAS  PubMed  Google Scholar 

  3. Choi, D. W. Calcium and excitotoxic neuronal injury. Ann. NY Acad. Sci. 747, 162–171 (1994).

    CAS  PubMed  Google Scholar 

  4. Brehm, P. & Eckert, R. Calcium entry leads to inactivation of calcium channel in Paramecium. Science 202, 1203–1206 (1978).

    CAS  PubMed  Google Scholar 

  5. Tillotson, D. Inactivation of Ca conductance dependent on entry of Ca ions in molluscan neurons. Proc. Natl Acad. Sci. USA 76, 1497–1500 (1979).References 4 and 5 are pioneering descriptions of CDI in Paramecium and molluscan neurons, and have directed the study of Ca2+ channels towards the analysis of localized Ca2+ signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee, A. et al. Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 399, 155–159 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. 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  PubMed  Google Scholar 

  8. Qin, N., Olcese, R., Bransby, M., Lin, T. & Birnbaumer, L. Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin. Proc. Natl Acad. Sci. USA 96, 2435–2438 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zühlke, R. D., Pitt, G. S., Deisseroth, K., Tsien, R. W. & Reuter, H. Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature 399, 159–162 (1999).References 6–9 show for the first time that CaM is essential for the inactivation of L- and P/Q-type Ca2+ channels.

    PubMed  Google Scholar 

  10. Hering, S. et al. Molecular determinants of inactivation in voltage-gated Ca2+ channels. J. Physiol. (Lond.) 528, 237–249 (2000).

    CAS  Google Scholar 

  11. Stotz, S. C. & Zamponi, G. W. Structural determinants of fast inactivation of high voltage-activated Ca2+ channels. Trends Neurosci. 24, 176–181 (2001).

    CAS  PubMed  Google Scholar 

  12. Eckert, R. & Tillotson, D. L. Calcium-mediated inactivation of the calcium conductance in caesium-loaded giant neurones of Aplysia californica. J. Physiol. (Lond.) 314, 265–280 (1981).

    CAS  PubMed Central  Google Scholar 

  13. Deitmer, J. W. Evidence for two voltage-dependent calcium currents in the membrane of the ciliate Stylonychia. J. Physiol. (Lond.) 355, 137–159 (1984).

    CAS  Google Scholar 

  14. McDonald, T. F., Pelzer, S., Trautwein, W. & Pelzer, D. J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 74, 365–507 (1994).

    CAS  PubMed  Google Scholar 

  15. Gera, S. & Byerly, L. Measurement of calcium channel inactivation is dependent upon the test pulse potential. Biophys. J. 76, 3076–3088 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Nägerl, U. V. & Mody, I. Calcium-dependent inactivation of high-threshold calcium currents in human dentate gyrus granule cells. J. Physiol. (Lond.) 509, 39–45 (1998).

    Google Scholar 

  17. Patil, P. G., Brody, D. L. & Yue, D. T. Preferential closed-state inactivation of neuronal calcium channels. Neuron 20, 1027–1038 (1998).

    CAS  PubMed  Google Scholar 

  18. Jones, S. W. & Marks, T. N. Calcium currents in bullfrog sympathetic neurons. II. Inactivation. J. Gen. Physiol. 94, 169–182 (1989).

    CAS  PubMed  Google Scholar 

  19. Jones, L. P., DeMaria, C. D. & Yue, D. T. N-type calcium channel inactivation probed by gating-current analysis. Biophys. J. 76, 2530–2552 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gera, S. & Byerly, L. Voltage- and calcium-dependent inactivation of calcium channels in Lymnaea neurons. J. Gen. Physiol. 114, 535–550 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ferreira, G., Yi, J., Rios, E. & Shirokov, R. Ion-dependent inactivation of barium current through L-type calcium channels. J. Gen. Physiol. 109, 449–461 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kay, A. R. Inactivation kinetics of calcium currents of acutely dissociated CA1 pyramidal cells of the mature guinea-pig hippocampus. J. Physiol. (Lond.) 437, 27–48 (1991).This monograph provides a comprehensive analysis of native Ca2+ current inactivation in central neurons, and points to the importance of local Ca2+ domains for CDI.

    CAS  Google Scholar 

  23. Gutnick, M. J., Lux, H. D., Swandulla, D. & Zucker, H. Voltage-dependent and calcium-dependent inactivation of calcium channel current in identified snail neurones. J. Physiol. (Lond.) 412, 197–220 (1989).

    CAS  Google Scholar 

  24. Chad, J. E. & Eckert, R. An enzymatic mechanism for calcium current inactivation in dialysed Helix neurones. J. Physiol. (Lond.) 378, 31–51 (1986).This pioneering work provided the first mechanistic explanation for CDI in neurons.

    CAS  Google Scholar 

  25. Imredy, J. P. & Yue, D. T. Submicroscopic Ca2+ diffusion mediates inhibitory coupling between individual Ca2+ channels. Neuron 9, 197–207 (1992).This paper shows that Ca2+ currents are controlled not only by intrinsic channel properties, but also by local diffusive interactions between neighbouring channels.

    CAS  PubMed  Google Scholar 

  26. Johnson, B. D. & Byerly, L. A cytoskeletal mechanism for Ca2+ channel metabolic dependence and inactivation by intracellular Ca2+. Neuron 10, 797–804 (1993).

    CAS  PubMed  Google Scholar 

  27. Johnson, B. D. & Byerly, L. Ca2+ channel Ca2+-dependent inactivation in a mammalian central neuron involves the cytoskeleton. Pflugers Arch. 429, 14–21 (1994).References 26 and 27 introduced the cytoskeleton as a mediator of CDI in molluscan and mammalian neurons.

    CAS  PubMed  Google Scholar 

  28. Naraghi, M. & Neher, E. Linearized buffered Ca2+ diffusion in microdomains and its implications for calculation of [Ca2+] at the mouth of a calcium channel. J. Neurosci. 17, 6961–6973 (1997).This theoretical paper describes the development of standing Ca2+ gradients within hundreds of microseconds and a few hundred nanometres after Ca2+ channel opening. In addition, it shows that every Ca2+ buffer can be assigned a uniquely defined length constant as a measure of its ability to buffer calcium close to the channel.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yue, D. T., Backx, P. H. & Imredy, J. P. Calcium-sensitive inactivation in the gating of single calcium channels. Science 250, 1735–1738 (1990).

    CAS  PubMed  Google Scholar 

  30. Kalman, D., O'Lague, P. H., Erxleben, C. & Armstrong, D. L. Calcium-dependent inactivation of the dihydropyridine-sensitive calcium channels in GH3 cells. J. Gen. Physiol. 92, 531–548 (1988).

    CAS  PubMed  Google Scholar 

  31. Lacerda, A. E. et al. Normalization of current kinetics by interaction between the α1 and β subunits of the skeletal muscle dihydropyridine-sensitive Ca2+ channel. Nature 352, 527–530 (1991).

    CAS  PubMed  Google Scholar 

  32. Varadi, G., Lory, P., Schultz, D., Varadi, M. & Schwartz, A. Acceleration of activation and inactivation by the β subunit of the skeletal muscle calcium channel. Nature 352, 159–162 (1991).

    CAS  PubMed  Google Scholar 

  33. Hell, J. W. et al. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J. Cell Biol. 123, 949–962 (1993).

    CAS  PubMed  Google Scholar 

  34. Hell, J. W., Westenbroek, R. E., Elliott, E. M. & Catterall, W. A. Differential phosphorylation, localization, and function of distinct α1 subunits of neuronal calcium channels. Two size forms for class B, C, and D α1 subunits with different COOH-termini. Ann. NY Acad. Sci. 747, 282–293 (1994).

    CAS  PubMed  Google Scholar 

  35. Meuth, S., Budde, T. & Pape, H.-C. Differential control of high-voltage activated Ca2+ current components by a Ca2+-dependent inactivation mechanism in thalamic relay neurons. Thalamus Relat. Syst. 1, 31–38 (2001).

    CAS  Google Scholar 

  36. Zeilhofer, H. U., Blank, N. M., Neuhuber, W. L. & Swandulla, D. Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin. Neuroscience 95, 235–241 (2000).

    CAS  PubMed  Google Scholar 

  37. 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).This paper points to the possible functional significance of CDI and CDF in presynaptic neurotransmitter release.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lukyanetz, E. A., Piper, T. P. & Sihra, T. S. Calcineurin involvement in the regulation of high-threshold Ca2+ channels in NG108-15 (rodent neuroblastoma × glioma hybrid) cells. J. Physiol. (Lond.) 510, 371–385 (1998). | PubMed |

    CAS  Google Scholar 

  39. Cox, D. H. & Dunlap, K. Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence. J. Gen. Physiol. 104, 311–336 (1994).

    CAS  PubMed  Google Scholar 

  40. Shirokov, R. Interaction between permeant ions and voltage sensor during inactivation of N-type Ca2+ channels. J. Physiol. (Lond.) 518, 697–703 (1999).

    CAS  Google Scholar 

  41. Sham, J. S., Cleemann, L. & Morad, M. Functional coupling of Ca2+ channels and ryanodine receptors in cardiac myocytes. Proc. Natl Acad. Sci. USA 92, 121–125 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Fabiato, A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am. J. Physiol. 245, C1–C14 (1983).

    CAS  PubMed  Google Scholar 

  43. Sun, H., Leblanc, N. & Nattel, S. Mechanisms of inactivation of L-type calcium channels in human atrial myocytes. Am. J. Physiol. 272, H1625–H1635 (1997).

    CAS  PubMed  Google Scholar 

  44. Chavis, P., Fagni, L., Lansman, J. B. & Bockaert, J. Functional coupling between ryanodine receptors and L-type calcium channels in neurons. Nature 382, 719–722 (1996).

    CAS  PubMed  Google Scholar 

  45. Berridge, M. J. Neuronal calcium signaling. Neuron 21, 13–26 (1998).

    CAS  PubMed  Google Scholar 

  46. Armstrong, D. L. Calcium channel regulation by calcineurin, a Ca2+-activated phosphatase in mammalian brain. Trends Neurosci. 12, 117–122 (1989).

    CAS  PubMed  Google Scholar 

  47. Hell, J. W. et al. Differential phosphorylation of two size forms of the neuronal class C L-type calcium channel α1 subunit. J. Biol. Chem. 268, 19451–19457 (1993).

    CAS  PubMed  Google Scholar 

  48. Hell, J. W. et al. N-methyl-d-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons. Proc. Natl Acad. Sci. USA 93, 3362–3367 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Rubin, C. S. A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP. Biochim. Biophys. Acta 1224, 467–479 (1994).

    PubMed  Google Scholar 

  50. Davare, M. A., Dong, F., Rubin, C. S. & Hell, J. W. The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons. J. Biol. Chem. 274, 30280–30287 (1999).

    CAS  PubMed  Google Scholar 

  51. Diviani, D. & Scott, J. D. AKAP signaling complexes at the cytoskeleton. J. Cell Sci. 114, 1431–1437 (2001).

    CAS  PubMed  Google Scholar 

  52. Theurkauf, W. E. & Vallee, R. B. Molecular characterization of the cAMP-dependent protein kinase bound to microtubule-associated protein 2. J. Biol. Chem. 257, 3284–3290 (1982).

    CAS  PubMed  Google Scholar 

  53. Meuth, S., Pape, H.-C. & Budde, T. Modulation of Ca2+ currents in rat thalamocortical relay neurons by activity and phosphorylation. Eur. J. Neurosci. 15, 1603–1614 (2002).

    PubMed  Google Scholar 

  54. Lukyanetz, E. A. Evidence for colocalization of calcineurin and calcium channels in dorsal root ganglion neurons. Neuroscience 78, 625–628 (1997).

    CAS  PubMed  Google Scholar 

  55. Branchaw, J. L., Banks, M. I. & Jackson, M. B. Ca2+- and voltage-dependent inactivation of Ca2+ channels in nerve terminals of the neurohypophysis. J. Neurosci. 17, 5772–5781 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Victor, R. G., Rusnak, F., Sikkink, R., Marban, E. & O'Rourke, B. Mechanism of Ca2+-dependent inactivation of L-type Ca2+ channels in GH3 cells: direct evidence against dephosphorylation by calcineurin. J. Membr. Biol. 156, 53–61 (1997).

    CAS  PubMed  Google Scholar 

  57. Burley, J. R. & Sihra, T. S. A modulatory role for protein phosphatase 2B (calcineurin) in the regulation of Ca2+ entry. Eur. J. Neurosci. 12, 2881–2891 (2000).

    CAS  PubMed  Google Scholar 

  58. Herzig, S. & Neumann, J. Effects of serine/threonine protein phosphatases on ion channels in excitable membranes. Physiol. Rev. 80, 173–210 (2000).

    CAS  PubMed  Google Scholar 

  59. Sculptoreanu, A., Rotman, E., Takahashi, M., Scheuer, T. & Catterall, W. A. Voltage-dependent potentiation of the activity of cardiac L-type calcium channel α1 subunits due to phosphorylation by cAMP-dependent protein kinase. Proc. Natl Acad. Sci. USA 90, 10135–10139 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hartzell, H. C., Hirayama, Y. & Petit-Jacques, J. Effects of protein phosphatase and kinase inhibitors on the cardiac L-type Ca current suggest two sites are phosphorylated by protein kinase A and another protein kinase. J. Gen. Physiol. 106, 393–414 (1995).

    CAS  PubMed  Google Scholar 

  61. Ono, K. & Fozzard, H. A. Two phosphatase sites on the Ca2+ channel affecting different kinetic functions. J. Physiol. (Lond.) 470, 73–84 (1993).

    CAS  Google Scholar 

  62. Davare, M. A., Horne, M. C. & Hell, J. W. Protein phosphatase 2A is associated with class C L-type calcium channels (Cav1.2) and antagonizes channel phosphorylation by cAMP-dependent protein kinase. J. Biol. Chem. 275, 39710–39717 (2000).

    CAS  PubMed  Google Scholar 

  63. Beck, H., Steffens, R., Heinemann, U. & Elger, C. E. Ca2+-dependent inactivation of high-threshold Ca2+ currents in hippocampal granule cells of patients with chronic temporal lobe epilepsy. J. Neurophysiol. 82, 946–954 (1999).

    CAS  PubMed  Google Scholar 

  64. Bennett, J. & Weeds, A. Calcium and the cytoskeleton. Br. Med. Bull. 42, 385–390 (1986).

    CAS  PubMed  Google Scholar 

  65. Hanlon, M. R., Berrow, N. S., Dolphin, A. C. & Wallace, B. A. Modelling of a voltage-dependent Ca2+ channel β subunit as a basis for understanding its functional properties. FEBS Lett. 445, 366–370 (1999).

    CAS  PubMed  Google Scholar 

  66. Sheng, M. & Wyszynski, M. Ion channel targeting in neurons. Bioessays 19, 847–853 (1997).

    CAS  PubMed  Google Scholar 

  67. Garner, C. C., Nash, J. & Huganir, R. L. PDZ domains in synapse assembly and signalling. Trends Cell Biol. 10, 274–280 (2000).

    CAS  PubMed  Google Scholar 

  68. Rosenmund, C. & Westbrook, G. L. Calcium-induced actin depolymerization reduces NMDA channel activity. Neuron 10, 805–814 (1993).

    CAS  PubMed  Google Scholar 

  69. Bickler, P. E. & Buck, L. T. Adaptations of vertebrate neurons to hypoxia and anoxia: maintaining critical Ca2+ concentrations. J. Exp. Biol. 201, 1141–1152 (1998).

    CAS  PubMed  Google Scholar 

  70. Sherman, A., Keizer, J. & Rinzel, J. Domain model for Ca2+-inactivation of Ca2+ channels at low channel density. Biophys. J. 58, 985–995 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Standen, N. B. & Stanfield, P. R. A binding-site model for calcium channel inactivation that depends on calcium entry. Proc. R. Soc. Lond. B 217, 101–110 (1982).

    CAS  PubMed  Google Scholar 

  72. Chad, J. E. & Eckert, R. Calcium domains associated with individual channels can account for anomalous voltage relations of Ca-dependent responses. Biophys. J. 45, 993–999 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Giannattasio, B., Jones, S. W. & Scarpa, A. Calcium currents in the A7r5 smooth muscle-derived cell line. Calcium-dependent and voltage-dependent inactivation. J. Gen. Physiol. 98, 987–1003 (1991).

    CAS  PubMed  Google Scholar 

  74. Zong, X. & Hofmann, F. Ca2+-dependent inactivation of the class C L-type Ca2+ channel is a property of the α1 subunit. FEBS Lett. 378, 121–125 (1996).

    CAS  PubMed  Google Scholar 

  75. Imredy, J. P. & Yue, D. T. Mechanism of Ca2+-sensitive inactivation of L-type Ca2+ channels. Neuron 12, 1301–1318 (1994).

    CAS  PubMed  Google Scholar 

  76. de Leon, M. et al. Essential Ca2+-binding motif for Ca2+-sensitive inactivation of L-type Ca2+ channels. Science 270, 1502–1506 (1995).This paper provided the first indication of the importance of the carboxy-terminal region of L-type Ca2+ channels for CDI.

    CAS  PubMed  Google Scholar 

  77. Zhou, J. et al. Feedback inhibition of Ca2+ channels by Ca2+ depends on a short sequence of the C terminus that does not include the Ca2+-binding function of a motif with similarity to Ca2+-binding domains. Proc. Natl Acad. Sci. USA 94, 2301–2305 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zühlke, R. D. & Reuter, H. Ca2+-sensitive inactivation of L-type Ca2+ channels depends on multiple cytoplasmic amino acid sequences of the α1C subunit. Proc. Natl Acad. Sci. USA 95, 3287–3294 (1998).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  80. Peterson, B. Z. et al. Critical determinants of Ca2+-dependent inactivation within an EF-hand motif of L-type Ca2+ channels. Biophys. J. 78, 1906–1920 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Anderson, M. E. Ca2+-dependent regulation of cardiac L-type Ca2+ channels: is a unifying mechanism at hand? J. Mol. Cell. Cardiol. 33, 639–650 (2001).

    CAS  PubMed  Google Scholar 

  82. Erickson, M. G., Alseikhan, B. A., Peterson, B. Z. & Yue, D. T. Preassociation of calmodulin with voltage-gated Ca2+ channels revealed by FRET in single living cells. Neuron 31, 973–985 (2001).By use of a modified FRET technique, the authors showed the constitutive association of CaM with several types of Ca2+ channel.

    CAS  PubMed  Google Scholar 

  83. 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).The authors present a model in which CaM is tethered at two sites to L-type Ca2+ channels and signals actively to slow inactivation. When the carboxy-terminal lobe of CaM binds to the nearby CaM-effector sequence (the IQ motif), the braking effect is relieved and CDI is accelerated.

    CAS  PubMed  Google Scholar 

  84. Romanin, C. et al. Ca2+ sensors of L-type Ca2+ channel. FEBS Lett. 487, 301–306 (2000).

    CAS  PubMed  Google Scholar 

  85. Pate, P. et al. Determinants for calmodulin binding on voltage-dependent Ca2+ channels. J. Biol. Chem. 275, 39786–39792 (2000).

    CAS  PubMed  Google Scholar 

  86. Soldatov, N. M., Oz, M., O'Brien, K. A., Abernethy, D. R. & Morad, M. Molecular determinants of L-type Ca2+ channel inactivation. Segment exchange analysis of the carboxyl-terminal cytoplasmic motif encoded by exons 40–42 of the human α1C subunit gene. J. Biol. Chem. 273, 957–963 (1998).

    CAS  PubMed  Google Scholar 

  87. 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).The surprising finding of this study is that the two competing processes of CDI and CDF both require Ca2+/CaM binding to a single IQ-like domain on the carboxyl tail of the Ca V 2.1 Ca2+ channel. The bifunctional capability of CaM arises from the bifurcation of Ca2+ signalling by the lobes of CaM.

    CAS  PubMed  Google Scholar 

  88. Zühlke, R. D., Pitt, G. S., Tsien, R. W. & Reuter, H. Ca2+-sensitive inactivation and facilitation of L-type Ca2+ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the α1C subunit. J. Biol. Chem. 275, 21121–21129 (2000).

    PubMed  Google Scholar 

  89. Davare, M. A. et al. A β2 adrenergic receptor signaling complex assembled with the Ca2+ channel CaV1.2. Science 293, 98–101 (2001).This paper impressively shows the existence of large multi-protein signalling complexes in mammalian central neurons, which provide highly localized, specific and rapid signalling by G-protein-coupled receptors.

    CAS  PubMed  Google Scholar 

  90. Hille, B. Ionic Channels of Excitable Membranes (Sinauer Associates, Sunderland, Massachusetts, 2001).

    Google Scholar 

  91. Baimbridge, K. G. & Miller, J. J. Hippocampal calcium-binding protein during commissural kindling-induced epileptogenesis: progressive decline and effects of anticonvulsants. Brain Res. 324, 85–90 (1984).

    CAS  PubMed  Google Scholar 

  92. Nägerl, U. V. et al. Surviving granule cells of the sclerotic human hippocampus have reduced Ca2+ influx because of a loss of calbindin-D28k in temporal lobe epilepsy. J. Neurosci. 20, 1831–1836 (2000).This paper points to the possible neuroprotective role of CDI in temporal lobe epilepsy, and highlights the ability of exogenous calbindin-D 28k to disrupt the CDI mechanism in hippocampal neurons.

    PubMed  PubMed Central  Google Scholar 

  93. Cens, T., Restituito, S., Galas, S. & Charnet, P. Voltage and calcium use the same molecular determinants to inactivate calcium channels. J. Biol. Chem. 274, 5483–5490 (1999).

    CAS  PubMed  Google Scholar 

  94. 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  PubMed  Google Scholar 

  95. Xiao, R. P., Cheng, H., Lederer, W. J., Suzuki, T. & Lakatta, E. G. Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx. Proc. Natl Acad. Sci. USA 91, 9659–9663 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Wu, Y., Dzhura, I., Colbran, R. J. & Anderson, M. E. Calmodulin kinase and a calmodulin-binding 'IQ' domain facilitate L-type Ca2+ current in rabbit ventricular myocytes by a common mechanism. J. Physiol. (Lond.) 535, 679–687 (2001).

    CAS  Google Scholar 

  97. Witcher, R. D. et al. Subunit identification and reconstitution of the N-type Ca2+ channel complex purified from brain. Science 261, 486–489 (1993).

    CAS  PubMed  Google Scholar 

  98. Dolphin, A. C. Mechanisms of modulation of voltage-dependent calcium channels by G proteins. J. Physiol. (Lond.) 506, 3–11 (1998).

    CAS  Google Scholar 

  99. Armstrong, C. M. & Hille, B. Voltage-gated ion channels and electrical excitability. Neuron 20, 371–380 (1998).

    CAS  PubMed  Google Scholar 

  100. Guerini, D. Calcineurin: not just a simple protein phosphatase. Biochem. Biophys. Res. Commun. 235, 271–275 (1997).

    CAS  PubMed  Google Scholar 

  101. Saimi, Y. & Kung, C. Calmodulin as an ion channel subunit. Annu. Rev. Physiol. 64, 289–311 (2002).

    CAS  PubMed  Google Scholar 

  102. Heizmann, C. W. Calcium signaling in the brain. Acta Neurobiol. Exp. (Warsz.) 53, 15–23 (1993).

    CAS  Google Scholar 

  103. Meuth, S., Pape, H.-C. & Budde, T. in Göttingen Neurobiology Report 2001 (eds Elsner, N. & Kreutzberg, G. W.) 837 (Thieme, Stuttgart, 2001).

    Google Scholar 

  104. Meyers, M. B. et al. Sorcin associates with the pore-forming subunit of voltage-dependent L-type Ca2+ channels. J. Biol. Chem. 273, 18930–18935 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft and Kultusministerium LSA. We thank E. D. Gundelfinger for critical reading of the manuscript before submission, and R. Ziegler for continuous assistance in our work.

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Authors and Affiliations

  1. Otto-von-Guericke-Universität, Institute of Physiology, Leipziger Straβe 44, Magdeburg, D-39120, Germany

    Thomas Budde, Sven Meuth & Hans-Christian Pape

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  1. Thomas Budde
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  2. Sven Meuth
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  3. Hans-Christian Pape
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Corresponding author

Correspondence to Thomas Budde.

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DATABASES

LocusLink

calbindin-D28k

calmodulin

calpain

calretinin

CaMKII

MAP2B

parvalbumin

PKA

PP1

PP2A

PP2B

sorcin

α1-subunit

α2-subunit

β-subunit

γ-subunit

FURTHER INFORMATION

Encyclopedia of Life Sciences

calcium and neurotransmitter release

calcium channel diversity

calcium channels

calcium signalling and regulation of cell function

calcium-binding proteins

EF-hand calcium-binding proteins

sodium, calcium and potassium channels 

Institut für Physiologie

The Ion Channel Web Page

Glossary

GH3 CELLS

A neural cell line that is derived from the rat anterior pituitary gland.

EF HAND

A Ca2+-binding domain, originally identified in parvalbumin, that is also known as the helix–loop–helix domain. The loop can accommodate Ca2+ by coordination through several amino acids in a pentagonal pyramid.

IQ MOTIF

A small structural domain that mediates interactions with calmodulin. The motif only loosely defines the amino-acid sequence at 5 of 11 possible residues. Different IQ domains bind calmodulin at varying intracellular Ca2+ concentrations or independently of Ca2+.

IFM MOTIF

A cluster of three hydrophobic amino acids located within the inactivation loop between domains III and IV that is required for fast Na+ channel inactivation.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

SH3 DOMAIN

Src-homology domains are involved in interactions with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).

WHOLE-CELL PATCH-CLAMP RECORDING

A high-resolution electrophysiological recording technique in which a very small electrode tip is sealed onto a patch of cell membrane and, with suction, the membrane patch is ruptured to allow low-resistance electrical access to the cell interior. Electrical currents flowing across the cell membrane can then be recorded, although the ion composition of the cell interior is altered to that of the electrode-filling solution.

DOMINANT NEGATIVE

Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A spectroscopic technique that is based on the transfer of energy from the excited state of a donor moiety to an acceptor. The transfer efficiency depends on the distance between the donor and the acceptor. FRET is often used to estimate distances between macromolecular sites in the 20–100-Å range, or to study interactions between macromolecules in vivo.

CB DOMAIN

A carboxy-terminal 26-amino-acid sequence found in L-type Ca2+ channels that binds calmodulin at low concentrations of intracellular Ca2+.

1-8-14 MOTIF

A consensus calmodulin-binding motif that is found, for example, in calcineurin (type A) and fodrin (type B).

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Budde, T., Meuth, S. & Pape, HC. Calcium-dependent inactivation of neuronal calcium channels. Nat Rev Neurosci 3, 873–883 (2002). https://doi.org/10.1038/nrn959

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