Papers of the Week

The auxiliary αδ subunits of voltage-gated calcium (Ca) channels are key to augmenting expression and function of Ca1 and Ca2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The αδ proteins are translated as preproteins encoding both α and δ, and post-translationally proteolyzed into α 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-αδ-1 and αδ-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 αδ-1 and αδ-3 is markedly reduced in cell lines by knockout of but not . 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 αδ is essential for the enhancement of Ca function, and in agreement, knockout of ADAM17 inhibited the ability of αδ-1 to enhance both Ca2.2 and Ca1.2 calcium currents. Finally, our data also indicate that the main site of proteolytic cleavage of αδ-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 αδ-1 and αδ-3, and thus a potential drug target in neuropathic pain.