ADAM17 mediates proteolytic maturation of voltage-gated calcium channel auxiliary α2δ subunits, and enables calcium current enhancement

Kadurin, Ivan, Dahimene, Shehrazade, Page, Karen M., Ellaway, Joseph I. J., Chaggar, Kanchan, Troeberg, Linda ORCID:, Nagase, Hideaki and Dolphin, Annette C. (2022) ADAM17 mediates proteolytic maturation of voltage-gated calcium channel auxiliary α2δ subunits, and enables calcium current enhancement. Function, 3 (3). ISSN 2633-8823

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The auxiliary α2δsubunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function of CaV1 and CaV2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The α2δproteins are translated as preproteins encoding both α2 and δ, and post-translationally proteolyzed into α2 and δsubunits, which remain associated as a complex. In this study, we have identified ADAM17 as a key protease involved in proteolytic processing of pro-α2δ-1 and α2δ-3 subunits. We provide three lines of evidence: First, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Second, proteolytic cleavage of both α2δ-1 and α2δ-3 is markedly reduced in cell lines by knockout of ADAM17 but not ADAM10. Third, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature α2δis essential for the enhancement of CaV function, and in agreement, knockout of ADAM17 inhibited the ability of α2δ-1 to enhance both CaV2.2 and CaV1.2 calcium currents. Finally, our data also indicate that the main site of proteolytic cleavage of α2δ-1 is the Golgi apparatus, although cleavage may also occur at the plasma membrane. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of α2δ-1 and α2δ-3, and thus a potential drug target in neuropathic pain.

Item Type: Article
Uncontrolled Keywords: calcium channel,alpha(2)delta subunit,matrix metalloprotease,adam17,trafficking,calcium currents,alpha-converting-enzyme,endoplasmic-reticulum,binding-site,trafficking,expression,protein,identification,physiology,timp-3,gene,α δsubunit,molecular medicine,physiology,cancer research,cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 06 May 2022 03:56
Last Modified: 19 Oct 2023 03:19
DOI: 10.1093/function/zqac013


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