Kadurin, Ivan;
Dahimene, Shehrazade;
Page, Karen M;
Ellaway, Joseph IJ;
Chaggar, Kanchan;
Troeberg, Linda;
Nagase, Hideaki;
(2022)
ADAM17 Mediates Proteolytic Maturation of Voltage-Gated Calcium Channel Auxiliary α2δ Subunits, and Enables Calcium Current Enhancement.
Function
, 3
(3)
, Article zqac013. 10.1093/function/zqac013.
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Abstract
The auxiliary α2δ subunits 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 α2δ proteins are translated as preproteins encoding both α2 and δ, and post-translationally proteolyzed into α2 and δ subunits, 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 α2δ is 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.
| Type: | Article |
|---|---|
| Title: | ADAM17 Mediates Proteolytic Maturation of Voltage-Gated Calcium Channel Auxiliary α2δ Subunits, and Enables Calcium Current Enhancement |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/function/zqac013 |
| Publisher version: | https://doi.org/10.1093/function/zqac013 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | ADAM17, calcium channel, calcium currents, matrix metalloprotease, trafficking, α2δ subunit |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10147803 |
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