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  • Review Article
  • Published:

Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond

Nature Reviews Neuroscience volume 13, pages 542–555 (2012)Cite this article

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An Erratum to this article was published on 25 July 2012

This article has been updated

Key Points

  • The voltage-gated calcium channels (VGCCs) consist of three subfamilies (CaV1, CaV2 and CaV3) that are defined by their pore-forming α1 subunits. The CaV1 and CaV2 families also contain the auxiliary α2δ and β subunits.

  • α2δ and β subunits increase the expression of functional calcium channels at the plasma membrane by different mechanisms and also influence the channels' biophysical properties. The β subunit binds to an intracellular linker on the α1 subunits and reduces their endoplasmic reticulum-associated proteasomal degradation, allowing forward trafficking of the channels, whereas the α2δ subunit is likely to act at a later stage in trafficking, in a process involving the VWA domain.

  • Accumulating evidence indicates that both the α2δ and the β subunits of VGCCs may also have roles that are not directly linked to calcium channel function. Some of these roles are associated with targeting or tethering the channels to specific microdomains, in particular presynaptic active zones, but other roles seem not to be associated with calcium channels.

  • The additional roles of the α2δ subunits involve interactions with other proteins, such as extracellular matrix and other membrane proteins. Indeed, this subunit may be involved in establishing the morphology of synapses.

  • Evidence indicates that specific β subunit splice variants may act in the nucleus as transcriptional regulators.

Abstract

The voltage-gated calcium channel α2δ and β subunits are traditionally considered to be auxiliary subunits that enhance channel trafficking, increase the expression of functional calcium channels at the plasma membrane and influence the channels' biophysical properties. Accumulating evidence indicates that these subunits may also have roles in the nervous system that are not directly linked to calcium channel function. For example, β subunits may act as transcriptional regulators, and certain α2δ subunits may function in synaptogenesis. The aim of this Review is to examine both the classic and novel roles for these auxiliary subunits in voltage-gated calcium channel function and beyond.

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Figure 1: Distribution and roles of calcium channels in neurons.
Figure 2: Voltage-gated calcium channel subunits.
Figure 3: Domains in α2δ subunits.
Figure 4: New roles for α2δ subunits may affect neuronal function independently from their role as calcium channel subunits.
Figure 5: β subunit interactions and effects on calcium channel.
Figure 6: Overview of the effects of α2δ and β subunits on calcium channel trafficking.

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Change history

  • 25 July 2012

    On page 551 of this article, the subunit labelled 'β2δ' in figure 6 should have been labelled 'α2δ'.

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Acknowledgements

The author's work is funded by the Wellcome Trust and the Medical Research Council. She would like to thank all members of her laboratory, past and present, who have contributed to work on this topic.

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    Annette C. Dolphin

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A.C.D. received a grant from Pfizer to fund a Ph.D. studentship.

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Glossary

Auxiliary subunits

In the context of ion channels, an auxiliary or accessory subunit does not have a direct role in forming the channel pore, but modifies the channels, affecting their trafficking, biophysical properties or pharmacology.

von Willebrand factor A domain

(VWA domain). These domains are found in many proteins, including integrins, and are generally involved in extracellular protein–protein interactions.

Metal ion-dependent adhesion site motif

(MIDAS motif). A motif located within the von Willebrand factor A domain. It binds a divalent cation, usually Ca2+ or Mg2+, to mediate high-affinity interactions with another protein, and is often associated with structural rearrangements.

Synaptogenesis

Synaptogenesis involves the formation of synapses between a presynaptic terminal and a postsynaptic element. It results in the close apposition of presynaptic active zones, which contain calcium channels and vesicular release sites, with postsynaptic membranes, which contain neurotransmitter receptor ion channels and other postsynaptic proteins.

Gabapentinoid

The drugs gabapentin and pregabalin are collectively termed gabapentinoids, which are also known as α2δ ligand drugs.

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Dolphin, A. Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond. Nat Rev Neurosci 13, 542–555 (2012). https://doi.org/10.1038/nrn3311

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