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A channelopathy mechanism revealed by direct calmodulin activation of TrpV4

Author:
Loukin, Stephen H., Teng, Jinfeng, Kung, Ching
Source:
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.30 pp. 9400-9405
ISSN:
0027-8424
Subject:
alleles, calcium, calmodulin, death, mutants, mutation, transient receptor potential channels
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. Ca ²⁺ encourages TrpV4 opening through calmodulin (CaM). Here, we examined two channels mutated in close proximity to the Ca ²⁺-CaM–binding domain. They not only leak but also are greatly reduced in activation by Ca ²⁺-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 Ca ²⁺-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.
Agid:
3387315