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Proc Natl Acad Sci U S A 2015 Jul 28;11230:9400-5. doi: 10.1073/pnas.1510602112.
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A channelopathy mechanism revealed by direct calmodulin activation of TrpV4.

Loukin SH , Teng J , Kung C .

Ca(2+)-calmodulin (CaM) regulates varieties of ion channels, including Transient Receptor Potential vanilloid subtype 4 (TrpV4). It has previously been proposed that internal Ca(2+) increases TrpV4 activity through Ca(2+)-CaM binding to a C-terminal Ca(2+)-CaM binding domain (CBD). We confirmed this model by directly presenting Ca(2+)-CaM protein to membrane patches excised from TrpV4-expressing oocytes. Over 50 TRPV4 mutations are now known to cause heritable skeletal dysplasia (SD) and other diseases in human. We have previously examined 14 SD alleles and found them to all have gain-of-function effects, with the gain of constitutive open probability paralleling disease severity. Among the 14 SD alleles examined, E797K and P799L are located immediate upstream of the CBD. They not only have increase basal activity, but, unlike the wild-type or other SD-mutant channels examined, they were greatly reduced in their response to Ca(2+)-CaM. Deleting a 10-residue upstream peptide (Δ795-804) that covers the two SD mutant sites resulted in strong constitutive activity and the complete lack of Ca(2+)-CaM response. We propose that the region immediately upstream of CBD is an autoinhibitory domain that maintains the closed state through electrostatic interactions, and adjacent detachable Ca(2+)-CaM binding to CBD sterically interferes with this autoinhibition. This work further supports the notion that TrpV4 mutations cause SD by constitutive leakage. However, the closed conformation is likely destabilized by various mutations by different mechanisms, including the permanent removal of an autoinhibition documented here.

PubMed ID: 26170305
PMC ID: PMC4522800
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: trpv1 trpv4

Disease Ontology terms: bone development disease

Article Images: [+] show captions
References [+] :
Adelman, SK channels and calmodulin. 2016, Pubmed