A channelopathy mechanism revealed by direct calmodulin activation of TrpV4
Abstract
Over 50 mutations in the ion channel Transient Receptor Potential vanilloid subtype 4 (TrpV4) cause diseases ranging from dwarfism to prenatal death. We previously examined 14 mutant channels and found them to leak. Ca2+ encourages TrpV4 opening through calmodulin (CaM). Here, we examined two channels mutated in close proximity to the Ca2+-CaM-binding domain. They not only leak but also are greatly reduced in activation by Ca2+-CaM compared with the wild-type or other mutant channels. These mutations likely define an autoinhibitory domain that keeps the channel closed, to which adjacent detachable Ca2+-CaM binding interferes with this inhibition. The scattered disease alleles may all make the channel leak but apparently by different means, including the loss of an autoinhibition shown here.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- July 2015
- DOI:
- 10.1073/pnas.1510602112
- Bibcode:
- 2015PNAS..112.9400L