Skip to main content
SpringerLink
Log in

The voltage-gated calcium-channel β subunit: more than just an accessory

  • Review
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

Abstract

Voltage-gated Ca2+ channels (VGCCs) are involved in a number of excitatory processes in the cell that regulate muscle contraction, neurotransmitter release, gene regulation, and neuronal migration. They consist of a central pore-forming α1 subunit together with a number of associated auxiliary subunits including a cytoplasmic β subunit. With the aid of X-ray crystallography, it has been found that the β subunits of VGCCs (β2a, β3, and β4) interact strongly with the I–II loop of the pore-forming α1 subunit. Here we discuss the potential interaction sites of β1a with its α1 subunit as well as the skeletal ryanodine receptor. We suggest that not only can β1a interact with the α1 subunit I–II loop, but more subtle interactions may be possible through the II–III loop via the β1a SH3 domain. Such findings could have important implications with respect to EC coupling.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ball SL, Powers PA, Shin HS, Morgans CW, Peachey NS, Gregg RG (2002) Role of the beta(2) subunit of voltage-dependent calcium channels in the retinal outer plexiform layer. Invest Ophthalmol Vis Sci 43:1595–1603

    PubMed  Google Scholar 

  • Beguin P, Nagashima K, Gonoi T, Shibasaki T, Takahashi K, Kashima Y, Ozaki N, Geering K, Iwanaga T, Seino S (2001) Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 411:701–706. doi:10.1038/35079621

    Article  PubMed  CAS  Google Scholar 

  • Beurg M, Ahern CA, Vallejo P, Conklin MW, Powers PA, Gregg RG, Coronado R (1999) Involvement of the carboxy-terminus region of the dihydropyridine receptor beta1a subunit in excitation–contraction coupling of skeletal muscle. Biophys J 77:2953–2967. doi:10.1016/S0006-3495(99)77128-6

    Article  PubMed  CAS  Google Scholar 

  • Bichet D, Cornet V, Geib S, Carlier E, Volsen S, Hoshi T, Mori Y, De Waard M (2000) The I–II loop of the Ca2+ channel alpha1 subunit contains an endoplasmic reticulum retention signal antagonized by the beta subunit. Neuron 25:177–190. doi:10.1016/S0896-6273(00)80881-8

    Article  PubMed  CAS  Google Scholar 

  • Burgess DL, Biddlecome GH, McDonough SI, Diaz ME, Zilinski CA, Bean BP, Campbell KP, Noebels JL (1999) Beta subunit reshuffling modifies N- and P/Q-type Ca2+ channel subunit compositions in lethargic mouse brain. Mol Cell Neurosci 13:293–311. doi:10.1006/mcne.1999.0748

    Article  PubMed  CAS  Google Scholar 

  • Castellano A, Wei X, Birnbaumer L, Perez-Reyes E (1993a) Cloning and expression of a neuronal calcium channel beta subunit. J Biol Chem 268:12359–12366

    PubMed  CAS  Google Scholar 

  • Castellano A, Wei X, Birnbaumer L, Perez-Reyes E (1993b) Cloning and expression of a third calcium channel beta subunit. J Biol Chem 268:3450–3455

    PubMed  CAS  Google Scholar 

  • Chen YH, Li MH, Zhang Y, He LL, Yamada Y, Fitzmaurice A, Shen Y, Zhang H, Tong L, Yang J (2004) Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature 429:675–680. doi:10.1038/nature02641

    Article  PubMed  CAS  Google Scholar 

  • Cheng W, Altafaj X, Ronjat M, Coronado R (2005) Interaction between the dihydropyridine receptor Ca2+ channel beta-subunit and ryanodine receptor type 1 strengthens excitation–contraction coupling. Proc Natl Acad Sci USA 102:19225–19230. doi:10.1073/pnas.0504334102

    Article  PubMed  CAS  Google Scholar 

  • Chishti AH (1998) Function of p55 and its nonerythroid homologues. Curr Opin Hematol 5:116–121

    Article  PubMed  CAS  Google Scholar 

  • Colecraft HM, Alseikhan B, Takahashi SX, Chaudhuri D, Mittman S, Yegnasubramanian V, Alvania RS, Johns DC, Marban E, Yue DT (2002) Novel functional properties of Ca(2+) channel beta subunits revealed by their expression in adult rat heart cells. J Physiol 541:435–452. doi:10.1113/jphysiol.2002.018515

    Article  PubMed  CAS  Google Scholar 

  • Dolphin AC (2003) β subunits of voltage-gated calcium channels. J Bioenerg Biomembr 35:599–620. doi:10.1023/B:JOBB.0000008026.37790.5a

    Article  PubMed  CAS  Google Scholar 

  • Dubuis E, Rockliffe N, Hussain M, Boyett M, Wray D, Gawler D (2006) Evidence for multiple Src binding sites on the alpha1c L-type Ca2+ channel and their roles in activity regulation. Cardiovasc Res 69:391–401. doi:10.1016/j.cardiores.2005.11.006

    Article  PubMed  CAS  Google Scholar 

  • Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, Johnston J, Baloh R, Sander T, Meisler MH (2000) Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 66:1531–1539. doi:10.1086/302909

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald EM (2002) The presence of Ca2+ channel beta subunit is required for mitogen-activated protein kinase (MAPK)-dependent modulation of alpha1B Ca2+ channels in COS-7 cells. J Physiol 543:425–437. doi:10.1113/jphysiol.2002.022822

    Article  PubMed  CAS  Google Scholar 

  • Gerster U, Neuhuber B, Groschner K, Striessnig J, Flucher BE (1999) Current modulation and membrane targeting of the calcium channel alpha1C subunit are independent functions of the beta subunit. J Physiol 517(Pt 2):353–368. doi:10.1111/j.1469-7793.1999.0353t.x

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Gutierrez G, Miranda-Laferte E, Neely A, Hidalgo P (2007) The Src homology 3 domain of the beta-subunit of voltage-gated calcium channels promotes endocytosis via dynamin interaction. J Biol Chem 282:2156–2162. doi:10.1074/jbc.M609071200

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Gutierrez G, Miranda-Laferte E, Nothmann D, Schmidt S, Neely A, Hidalgo P (2008) The guanylate kinase domain of the beta-subunit of voltage-gated calcium channels suffices to modulate gating. Proc Natl Acad Sci USA 105:14198–14203. doi:10.1073/pnas.0806558105

    Article  PubMed  Google Scholar 

  • Hanlon MR, Berrow NS, Dolphin AC, Wallace BA (1999) Modelling of a voltage-dependent Ca2+ channel beta subunit as a basis for understanding its functional properties. FEBS Lett 445:366–370. doi:10.1016/S0014-5793(99)00156-8

    Article  PubMed  CAS  Google Scholar 

  • He LL, Zhang Y, Chen YH, Yamada Y, Yang J (2007) Functional modularity of the beta-subunit of voltage-gated Ca2+ channels. Biophys J 93:834–845. doi:10.1529/biophysj.106.101691

    Article  PubMed  CAS  Google Scholar 

  • Hullin R, Singer-Lahat D, Freichel M, Biel M, Dascal N, Hofmann F, Flockerzi V (1992) Calcium channel beta subunit heterogeneity: functional expression of cloned cDNA from heart, aorta and brain. EMBO J 11:885–890

    PubMed  CAS  Google Scholar 

  • Hullin R, Asmus F, Ludwig A, Hersel J, Boekstegers P (1999) Subunit expression of the cardiac L-type calcium channel is differentially regulated in diastolic heart failure of the cardiac allograft. Circulation 100:155–163

    PubMed  CAS  Google Scholar 

  • Hullin R, Khan IF, Wirtz S, Mohacsi P, Varadi G, Schwartz A, Herzig S (2003) Cardiac L-type calcium channel beta-subunits expressed in human heart have differential effects on single channel characteristics. J Biol Chem 278:21623–21630. doi:10.1074/jbc.M211164200

    Article  PubMed  CAS  Google Scholar 

  • Kimura T, Pace SM, Wei L, Beard NA, Dirksen RT, Dulhunty AF (2007) A variably spliced region in the type 1 ryanodine receptor may participate in an inter-domain interaction. Biochem J 401:317–324. doi:10.1042/BJ20060686

    Article  PubMed  CAS  Google Scholar 

  • Kistner U, Garner CC, Linial M (1995) Nucleotide binding by the synapse associated protein SAP90. FEBS Lett 359:159–163. doi:10.1016/0014-5793(95)00030-D

    Article  PubMed  CAS  Google Scholar 

  • Leuranguer V, Papadopoulos S, Beam KG (2006) Organization of calcium channel beta1a subunits in triad junctions in skeletal muscle. J Biol Chem 281:3521–3527. doi:10.1074/jbc.M509566200

    Article  PubMed  CAS  Google Scholar 

  • McPherson PS (1999) Regulatory role of SH3 domain-mediated protein–protein interactions in synaptic vesicle endocytosis. Cell Signal 11:229–238. doi:10.1016/S0898-6568(98)00059-X

    Article  PubMed  CAS  Google Scholar 

  • Neuhuber B, Gerster U, Mitterdorfer J, Glossmann H, Flucher BE (1998) Differential effects of Ca2+ channel beta1a and beta2a subunits on complex formation with alpha1S and on current expression in tsA201 cells. J Biol Chem 273:9110–9118. doi:10.1074/jbc.273.15.9110

    Article  PubMed  CAS  Google Scholar 

  • Obermair GJ, Tuluc P, Flucher BE (2008) Auxiliary Ca(2+) channel subunits: lessons learned from muscle. Curr Opin Pharmacol 8:311–318. doi:10.1016/j.coph.2008.01.008

    Article  PubMed  CAS  Google Scholar 

  • Opatowsky Y, Chomsky-Hecht O, Kang MG, Campbell KP, Hirsch JA (2003) The voltage-dependent calcium channel beta subunit contains two stable interacting domains. J Biol Chem 278:52323–52332. doi:10.1074/jbc.M303564200

    Article  PubMed  CAS  Google Scholar 

  • Opatowsky Y, Chen CC, Campbell KP, Hirsch JA (2004) Structural analysis of the voltage-dependent calcium channel beta subunit functional core and its complex with the alpha 1 interaction domain. Neuron 42:387–399. doi:10.1016/S0896-6273(04)00250-8

    Article  PubMed  CAS  Google Scholar 

  • Perez-Reyes E, Castellano A, Kim HS, Bertrand P, Baggstrom E, Lacerda AE, Wei XY, Birnbaumer L (1992) Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel. J Biol Chem 267:1792–1797

    PubMed  CAS  Google Scholar 

  • Qin N, Platano D, Olcese R, Stefani E, Birnbaumer L (1997) Direct interaction of gbetagamma with a C-terminal gbetagamma-binding domain of the Ca2+ channel alpha1 subunit is responsible for channel inhibition by G protein-coupled receptors. Proc Natl Acad Sci USA 94:8866–8871. doi:10.1073/pnas.94.16.8866

    Article  PubMed  CAS  Google Scholar 

  • Raghib A, Bertaso F, Davies A, Page KM, Meir A, Bogdanov Y, Dolphin AC (2001) Dominant-negative synthesis suppression of voltage-gated calcium channel Cav2.2 induced by truncated constructs. J Neurosci 21:8495–8504

    PubMed  CAS  Google Scholar 

  • Richards MW, Butcher AJ, Dolphin AC (2004) Ca2+ channel beta-subunits: structural insights AID our understanding. Trends Pharmacol Sci 25:626–632. doi:10.1016/j.tips.2004.10.008

    Article  PubMed  CAS  Google Scholar 

  • Richards MW, Leroy J, Pratt WS, Dolphin AC (2007) The HOOK-domain between the SH3 and the GK domains of Cavbeta subunits contains key determinants controlling calcium channel inactivation. Channels Austin 1:92–101

    PubMed  Google Scholar 

  • Ruth P, Rohrkasten A, Biel M, Bosse E, Regulla S, Meyer HE, Flockerzi V, Hofmann F (1989) Primary structure of the beta subunit of the DHP-sensitive calcium channel from skeletal muscle. Science 245:1115–1118. doi:10.1126/science.2549640

    Article  PubMed  CAS  Google Scholar 

  • Schredelseker J, Di Biase V, Obermair GJ, Felder ET, Flucher BE, Franzini-Armstrong C, Grabner M (2005) The beta 1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle. Proc Natl Acad Sci USA 102:17219–17224. doi:10.1073/pnas.0508710102

    Article  PubMed  CAS  Google Scholar 

  • Schredelseker J, Dayal A, Schwerte T, Franzini-Armstrong C, Grabner M (2009) Proper restoration of excitation-contraction coupling in the dihydropyridine receptor beta 1-null zebrafish relaxed is an exclusive function of the beta 1a subunit. J Biol Chem 284:1242–1251

    Article  PubMed  CAS  Google Scholar 

  • Sheridan DC, Cheng W, Carbonneau L, Ahern CA, Coronado R (2004) Involvement of a heptad repeat in the carboxyl terminus of the dihydropyridine receptor beta1a subunit in the mechanism of excitation–contraction coupling in skeletal muscle. Biophys J 87:929–942. doi:10.1529/biophysj.104.043810

    Article  PubMed  CAS  Google Scholar 

  • Stephens GJ, Page KM, Bogdanov Y, Dolphin AC (2000) The alpha1B Ca2+ channel amino terminus contributes determinants for beta subunit-mediated voltage-dependent inactivation properties. J Physiol 525(Pt 2):377–390. doi:10.1111/j.1469-7793.2000.t01-1-00377.x

    Article  PubMed  CAS  Google Scholar 

  • Strube C, Beurg M, Powers PA, Gregg RG, Coronado R (1996) Reduced Ca2+ current, charge movement, and absence of Ca2+ transients in skeletal muscle deficient in dihydropyridine receptor beta 1 subunit. Biophys J 71:2531–2543. doi:10.1016/S0006-3495(96)79446-8

    Article  PubMed  CAS  Google Scholar 

  • Takahashi M, Seagar MJ, Jones JF, Reber BFX, Catterall WA (1987) Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc Natl Acad Sci USA 84:5478–5482. doi:10.1073/pnas.84.15.5478

    Article  PubMed  CAS  Google Scholar 

  • Tanabe T, Beam KG, Adams BA, Niidome T, Numa S (1990) Regions of the skeletal muscle dihydropyridine receptor critical for excitation-contraction coupling. Nature 346:567–569

    Article  PubMed  CAS  Google Scholar 

  • Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr (2004) Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature 429:671–675. doi:10.1038/nature02588

    Article  PubMed  CAS  Google Scholar 

  • Van Petegem F, Duderstadt KE, Clark KA, Wang M, Minor DL Jr (2008) Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaValpha1 AID-CaVbeta interaction site that is critical for channel modulation. Structure 16:280–294. doi:10.1016/j.str.2007.11.010

    Article  PubMed  CAS  Google Scholar 

  • Walker D, Bichet D, Geib S, Mori E, Cornet V, Snutch TP, Mori Y, De Waard M (1999) A new beta subtype-specific interaction in alpha1A subunit controls P/Q-type Ca2+ channel activation. J Biol Chem 274:12383–12390. doi:10.1074/jbc.274.18.12383

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra, ACT, 2601, Australia

    Yamuna Karunasekara, Angela F. Dulhunty & Marco G. Casarotto

Authors
  1. Yamuna Karunasekara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angela F. Dulhunty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco G. Casarotto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco G. Casarotto.

Additional information

“Proteins, membranes and cells: the structure–function nexus.” Contributions from the annual scientific meeting (including a special symposium in honour of Professor Alex Hope of Flinders University, South Australia) of the Australian Society for Biophysics held in Canberra, ACT, Australia, 28 September–1 October 2008.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karunasekara, Y., Dulhunty, A.F. & Casarotto, M.G. The voltage-gated calcium-channel β subunit: more than just an accessory. Eur Biophys J 39, 75–81 (2009). https://doi.org/10.1007/s00249-009-0467-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-009-0467-4

Keywords

Search

Navigation