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.
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.
Angelotti, T., and Hofmann, F., (1996). FEBS Lett. 397, 331–337.
Bangalore, R., Mehrke, G., Gingrich, K., Hofmann, F., and Kass, R. S., (1996). Am. J. Physiol. 270, H1521–H1528.
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.
Beydoun, A., Uthman, B. M., and Sackellares, J. C., (1995). Clin. Neuropharmacol. 18, 469–481.
Bosse, E., Regulla, S., Biel, M., Ruth, P., Meyer, H. E., Flockerzi, V., and Hofmann, F., (1990). FEBS Lett. 267, 153–156.
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.
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.
Brown, J. P., Dissanayake, V. U., Briggs, A. R., Milic, M. R., and Gee, N. S., (1998). Anal. Biochem. 255, 236–243.
Brown, J. P., and Gee, N. S., (1998). J. Biol. Chem. 273, 25458–25465.
Calabresi, P., Centonze, M. G. A., Pisani, A., and Bernardi, G., (1999). Br. J. Pharmacol. 126, 689–696.
Catterall, W. A., (2000). Annu. Rev. Cell Dev. Biol. 16, 521–555.
De Jongh, K. S., Warner, C., and Catterall W. A., (1990). J. Biol. Chem. 265, 14738–14741.
De Waard, M., and Campbell, K. P., (1995). J. Physiol. (Lond.), 485, 619–634.
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.
Dooley, D. J., Donovan, C. M., and Pugsley, T. A. J., (2000). J. Pharmacol. Exp. Ther. 295, 1086–1093.
Eberst, R., Dai, S., Klugbauer, N., and Hofmann, F., (1997). Pflüg. Arch. 433, 633–637.
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.
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.
Felix, R., (1999). Recept. Channels, 6, 351–362.
Felix, R., Gurnett, C. A., De Waard, M., and Campbell, K. P., (1997). J. Neurosci. 17, 6884–6891.
Fink, K., Meder, W., Dooley, D. J., and Göthert, M., (2000). Br. J. Pharmacol. 130, 900–906.
Fink, K., Dooley, D. J., Meder, W. P., Suman-Chauhan, N., Duffy, S., Clusmann, H., and Göthert, M., (2002). Neuropharmacology, 42, 229–236.
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.
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.
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.
Gong, H. C., Hang, J., Kohler, W., Li, L., and Su, T.-Z., (2001). J. Membr. Biol. 184, 35–43.
Gurnett, C. A., De Waard, M., and Campbell, K. P., (1996). Neuron, 16, 431–440.
Gurnett, C. A., Felix, R., and Campbell, K. P., (1997). J. Biol. Chem. 272, 18508–18512.
Hanke, S., Bugert, P., Chudek, J., and Kovacs, G., (2001). Gene, 264, 69–75.
Hobom, M., Dai, S., Marais, E., Lacinova, L., Hofmann, F., and Klugbauer, N., (2000). Eur. J. Neurosci. 12, 1217–1226.
Hofmann, F., Lacinova, L., and Klugbauer, N., (1999). Rev. Physiol. Biochem. Pharmacol. 139, 33–87.
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.
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.
Jones, L. P., Wei, S.-K., and Yue, D. T., (1998). J. Gen. Physiol. 112, 125–143.
Klugbauer, N., Dai, S., Specht, V., Lacinova, L., Marais, E., Bohn, G., and Hofmann, F., (2000). FEBS Lett. 470, 189–197.
Klugbauer, N., Lacinova, L., Marais, E., Hobom, M., and Hofmann, F., (1999). J. Neurosci. 19, 684–691.
Lacinova, L., Klugbauer, N., and Hofmann, F., (1999). J. Physiol. 516, 639–645.
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.
Marais, E., Klugbauer, N., and Hofmann, F., (2001). Mol. Pharmacol. 59, 1243–1248.
Morton, M. E., and Froehner S. C., (1989). Neuron, 2, 1499–1506.
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.
Parent, L., Schneider, T., Moore, C. P., and Talwar, D., (1997). J. Membr. Biol. 160, 127–140.
Puranam, H. A., and McNamara, J. O., (1999). Curr. Opin. Neurobiol. 9, 281–287.
Qin, N., Olcese, R., Stefani, E., and Birnbaumer, L., (1998). Am. J. Physiol. 274, C1324–C1331.
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.
Schumacher, T. B., Beck, H., Steinhäuser, C., Schramm, J., and Elger, C. E., (1998). Epilepsia, 39, 355–363.
Shirokov, R., Ferreira, G., Yi, J., and Rios, E., (1998). J. Gen. Physiol. 111, 807–823.
Shistik, E., Ivanina, T., Puri, T., Hosey, M., and Dascal, N., (1995). J. Physiol. (Lond.), 489, 55–62.
Singer, D., Biel, M., Lotan, I., Flockerzi, V., and Hofmann, F., (1991). Science, 253, 1553–1557.
Snell, G. D., (1955). J. Hered. 46, 27–29.
Stefani, A., Spadoni, F., and Bernardi, G., (1998). Neuropharmacology, 37, 83–91.
Taylor, M. T., and Bonhaus, D. W., (2000). Neuropharmacology, 39, 1267–1273.
Walker, D., and De Waard, M., (1998). Trends Neurosci. 21, 148–154.
Wang, M., Offord, J., Oxender, D. L., and Su, T.-Z., (1999). Biochem. J. 342, 313–320.
Welling, A., Bosse, E., Cavalie, A., Bottlender, G., Ludwig, A., Nastainczyk, W., Flockerzi, V., and Hofmann, F., (1993). Physiol. (Lond.), 471, 749–765.
Wiser, O., Trus, M., Tobi, D., Halevi, S., Giladi, E., and Atlas, D., (1996). FEBS Lett. 379, 15–20.
Author information
Authors and Affiliations
Rights 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
Issue Date:
DOI: https://doi.org/10.1023/B:JOBB.0000008028.41056.58