Skip to main content
Log in

Calcium Channel α2δ Subunits: Differential Expression, Function, and Drug Binding

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Voltage-activated calcium channels are transmembrane proteins that act as transducers of electrical signals into numerous intracellular activities. On the basis of their electrophysiological properties they are classified as high- and low-voltage-activated calcium channels. High-voltage-activated calcium channels are heterooligomeric proteins consisting of a pore-forming α1 subunit and auxiliary α2δ, β, and—in some tissues—γ subunits. Auxiliary subunits support the membrane trafficking of the α1 subunit and modulate the kinetic properties of the channel. In particular, the α2δ subunit has been shown to modify the biophysical and pharmacological properties of the α1 subunit. The α2δ subunit is posttranslationally cleaved to form disulfide-linked α2 and, δ proteins, both of which are heavily glycosylated. Recently it was shown that at least four genes encode for α2δ subunits which are expressed in a tissue-specific manner. Their biophysical properties were characterized in coexpression studies with high- and low-voltage-activated calcium channels. Mutations in the gene encoding α2δ-2 have been found to underlie the ducky phenotype. This mouse mutant is a model for absence epilepsy and is characterized by spike wave seizures and cerebellar ataxia. α2δ subunits can also support pharmacological interactions with drugs that are used for the treatment of epilepsy and neuropathic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Angeloni, D., Wei, M.-H., Duh, F.-M., Johnson, B. E., and Lerman, M. I., (2000). Mol. Cell. Probes, 14, 53–54.

    PubMed  Google Scholar 

  • Angelotti, T., and Hofmann, F., (1996). FEBS Lett. 397, 331–337.

    PubMed  Google Scholar 

  • Bangalore, R., Mehrke, G., Gingrich, K., Hofmann, F., and Kass, R. S., (1996). Am. J. Physiol. 270, H1521–H1528.

    Google Scholar 

  • Barclay, J., Balaguero, N., Mione, M., Ackerman, S. L., Letts, V. A., Brodbeck, J., Canti, C., Meir, A., Page K. M., Kusumi, K., Perez-Reyes, E., Lander E. S., Frankel, W. N., Gardiner, R. M., Dolphin, A. C., and Rees, M., (2001). J. Neurosci. 21, 6995–6104.

    Google Scholar 

  • Beydoun, A., Uthman, B. M., and Sackellares, J. C., (1995). Clin. Neuropharmacol. 18, 469–481.

    PubMed  Google Scholar 

  • Bosse, E., Regulla, S., Biel, M., Ruth, P., Meyer, H. E., Flockerzi, V., and Hofmann, F., (1990). FEBS Lett. 267, 153–156.

    PubMed  Google Scholar 

  • Brickley, K., Campbell, V., Berrow, N., Leach, R., Norman, RI., Wray, D., Dolphin, A. C., and Baldwin, S. A., (1995). FEBS Lett. 364, 129–133.

    PubMed  Google Scholar 

  • Brodbeck, J., Davies, A., Courtney, J.-M., Meir, A., Balaguero, N., Canti, C., Moss, F. J., Page, K. M., Pratt, W. S., Hunt, S. P., Barclay, J., Rees, M., and Dolphin, A. C., (2002). J. Biol. Chem. 277, 7684–7693.

    PubMed  Google Scholar 

  • Brown, J. P., Dissanayake, V. U., Briggs, A. R., Milic, M. R., and Gee, N. S., (1998). Anal. Biochem. 255, 236–243.

    PubMed  Google Scholar 

  • Brown, J. P., and Gee, N. S., (1998). J. Biol. Chem. 273, 25458–25465.

    PubMed  Google Scholar 

  • Calabresi, P., Centonze, M. G. A., Pisani, A., and Bernardi, G., (1999). Br. J. Pharmacol. 126, 689–696.

    PubMed  Google Scholar 

  • Catterall, W. A., (2000). Annu. Rev. Cell Dev. Biol. 16, 521–555.

    PubMed  Google Scholar 

  • De Jongh, K. S., Warner, C., and Catterall W. A., (1990). J. Biol. Chem. 265, 14738–14741.

    PubMed  Google Scholar 

  • De Waard, M., and Campbell, K. P., (1995). J. Physiol. (Lond.), 485, 619–634.

    Google Scholar 

  • Dolphin, A. C., Wyatt, C. N., Richards, J., Beattie, R. E., Craig, P., Lee, J.-H., Cribbs, L. L., Volsen, S. G., and Perez-Reyes, E., (1999). J. Physiol. 519, 35–45.

    PubMed  Google Scholar 

  • Dooley, D. J., Donovan, C. M., and Pugsley, T. A. J., (2000). J. Pharmacol. Exp. Ther. 295, 1086–1093.

    PubMed  Google Scholar 

  • Eberst, R., Dai, S., Klugbauer, N., and Hofmann, F., (1997). Pflüg. Arch. 433, 633–637.

    Google Scholar 

  • Ellis, S. B., Williams, M. E., Ways, N. R., Brenner, R., Sharp, A. H., Leung, A. T., Campbell, K. P., McKenna, E., Koch, W. J., Hui, A., Schwartz, A., and Harpold, M. M., (1988). Science, 241, 1661–1664.

    PubMed  Google Scholar 

  • Ertel, E. A., Campbell, K. P., Harpold, M. M., Hofmann, F., Mori, Y., Perez-Reyes, E., Schwartz, A., Snutch, T. P., Tanabe, T., Birnbaumer, L., Tsien, R. W., and Catterall, W. A., (2000). Neuron, 25, 533–535.

    PubMed  Google Scholar 

  • Felix, R., (1999). Recept. Channels, 6, 351–362.

    PubMed  Google Scholar 

  • Felix, R., Gurnett, C. A., De Waard, M., and Campbell, K. P., (1997). J. Neurosci. 17, 6884–6891.

    PubMed  Google Scholar 

  • Fink, K., Meder, W., Dooley, D. J., and Göthert, M., (2000). Br. J. Pharmacol. 130, 900–906.

    PubMed  Google Scholar 

  • Fink, K., Dooley, D. J., Meder, W. P., Suman-Chauhan, N., Duffy, S., Clusmann, H., and Göthert, M., (2002). Neuropharmacology, 42, 229–236.

    PubMed  Google Scholar 

  • Freise, D., Held, B., Wissenbach, U., Pfeifer, A., Trost, C., Himmerkus, N., Schweig, U., Freichel, M., Biel, M., Hofmann, F., Hoth, M., and Flockerzi, V., (2000). J. Biol. Chem. 275, 14476–14481.

    PubMed  Google Scholar 

  • Gao, B., Yoshitaka, S., Maximov, A., Saad, M., Forgacs, E., Latif, F., Wei, M. H., Lerman, M., Lee, J.-H., Perez-Reyes, E., Bezprozvanny, I., and Minna, J. D., (2000). J. Biol. Chem. 275, 12237–12242.

    PubMed  Google Scholar 

  • Gee, S. G., Brown, J. P., Dissanayake, V. U. K., Offord, J., Thurlow, R., and Woodruff, G. N., (1996). J. Biol. Chem. 271, 5768–5776.

    PubMed  Google Scholar 

  • Gong, H. C., Hang, J., Kohler, W., Li, L., and Su, T.-Z., (2001). J. Membr. Biol. 184, 35–43.

    PubMed  Google Scholar 

  • Gurnett, C. A., De Waard, M., and Campbell, K. P., (1996). Neuron, 16, 431–440.

    PubMed  Google Scholar 

  • Gurnett, C. A., Felix, R., and Campbell, K. P., (1997). J. Biol. Chem. 272, 18508–18512.

    PubMed  Google Scholar 

  • Hanke, S., Bugert, P., Chudek, J., and Kovacs, G., (2001). Gene, 264, 69–75.

    PubMed  Google Scholar 

  • Hobom, M., Dai, S., Marais, E., Lacinova, L., Hofmann, F., and Klugbauer, N., (2000). Eur. J. Neurosci. 12, 1217–1226.

    PubMed  Google Scholar 

  • Hofmann, F., Lacinova, L., and Klugbauer, N., (1999). Rev. Physiol. Biochem. Pharmacol. 139, 33–87.

    PubMed  Google Scholar 

  • Jay, S. D., Ellis, S. B., McCue, A. F., Williams, M. E., Vedvick, T. S., Harpold, M. M., and Campbell, K. P., (1990). Science, 248, 490–492.

    PubMed  Google Scholar 

  • Jay, S. D., Sharp, A. H., Kahl, S. D., Vedvick, T. S., Harpold, M. M., and Campbell, K. P., (1991). J. Biol. Chem. 266, 3287–3293.

    PubMed  Google Scholar 

  • Jones, L. P., Wei, S.-K., and Yue, D. T., (1998). J. Gen. Physiol. 112, 125–143.

    PubMed  Google Scholar 

  • Klugbauer, N., Dai, S., Specht, V., Lacinova, L., Marais, E., Bohn, G., and Hofmann, F., (2000). FEBS Lett. 470, 189–197.

    PubMed  Google Scholar 

  • Klugbauer, N., Lacinova, L., Marais, E., Hobom, M., and Hofmann, F., (1999). J. Neurosci. 19, 684–691.

    PubMed  Google Scholar 

  • Lacinova, L., Klugbauer, N., and Hofmann, F., (1999). J. Physiol. 516, 639–645.

    PubMed  Google Scholar 

  • Letts, V. A., Felix, R., Biddlecome, G. H., Arikkath, J., Mahaffey, C. L., Velanzuela, A., Bartlett, F. S., Mori, Y., Campbell, K. P., and Frankel, W. N., (1998). Nat. Genet. 19, 340–346.

    PubMed  Google Scholar 

  • Marais, E., Klugbauer, N., and Hofmann, F., (2001). Mol. Pharmacol. 59, 1243–1248.

    PubMed  Google Scholar 

  • Morton, M. E., and Froehner S. C., (1989). Neuron, 2, 1499–1506.

    PubMed  Google Scholar 

  • Ng, G. Y. K., Bertrand, S., Sullivan, R., Ethier, N., Wang, J., Yergey, J., Belley, M., Trimble, L., Bateman, K., and Alder, L., (2001). Mol. Pharmacol. 59, 144–152.

    PubMed  Google Scholar 

  • Parent, L., Schneider, T., Moore, C. P., and Talwar, D., (1997). J. Membr. Biol. 160, 127–140.

    PubMed  Google Scholar 

  • Puranam, H. A., and McNamara, J. O., (1999). Curr. Opin. Neurobiol. 9, 281–287.

    PubMed  Google Scholar 

  • Qin, N., Olcese, R., Stefani, E., and Birnbaumer, L., (1998). Am. J. Physiol. 274, C1324–C1331.

    PubMed  Google Scholar 

  • Qin, N., Yagel, S., Momplaisir, M.-L., Codd, E. E., and D'Andrea, M. R., (2002). Mol. Pharmacol. 62.

  • Rosenberg, J. M., Harrell, C., Ristic, H., Werner R. A., and deRosayro, A. M., (1997). Clin. J. Pain, 13, 251–255.

    PubMed  Google Scholar 

  • Schumacher, T. B., Beck, H., Steinhäuser, C., Schramm, J., and Elger, C. E., (1998). Epilepsia, 39, 355–363.

    PubMed  Google Scholar 

  • Shirokov, R., Ferreira, G., Yi, J., and Rios, E., (1998). J. Gen. Physiol. 111, 807–823.

    PubMed  Google Scholar 

  • Shistik, E., Ivanina, T., Puri, T., Hosey, M., and Dascal, N., (1995). J. Physiol. (Lond.), 489, 55–62.

    Google Scholar 

  • Singer, D., Biel, M., Lotan, I., Flockerzi, V., and Hofmann, F., (1991). Science, 253, 1553–1557.

    PubMed  Google Scholar 

  • Snell, G. D., (1955). J. Hered. 46, 27–29.

    Google Scholar 

  • Stefani, A., Spadoni, F., and Bernardi, G., (1998). Neuropharmacology, 37, 83–91.

    PubMed  Google Scholar 

  • Taylor, M. T., and Bonhaus, D. W., (2000). Neuropharmacology, 39, 1267–1273.

    PubMed  Google Scholar 

  • Walker, D., and De Waard, M., (1998). Trends Neurosci. 21, 148–154.

    PubMed  Google Scholar 

  • Wang, M., Offord, J., Oxender, D. L., and Su, T.-Z., (1999). Biochem. J. 342, 313–320.

    PubMed  Google Scholar 

  • Welling, A., Bosse, E., Cavalie, A., Bottlender, G., Ludwig, A., Nastainczyk, W., Flockerzi, V., and Hofmann, F., (1993). Physiol. (Lond.), 471, 749–765.

    Google Scholar 

  • Wiser, O., Trus, M., Tobi, D., Halevi, S., Giladi, E., and Atlas, D., (1996). FEBS Lett. 379, 15–20.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klugbauer, N., Marais, E. & Hofmann, F. Calcium Channel α2δ Subunits: Differential Expression, Function, and Drug Binding. J Bioenerg Biomembr 35, 639–647 (2003). https://doi.org/10.1023/B:JOBB.0000008028.41056.58

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:JOBB.0000008028.41056.58

Navigation