ArticleProceedings of the National Academy of Sciences of the United States of America2015
A channelopathy mechanism revealed by direct calmodulin activation of TrpV4.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Drafting the calmodulation playbook: Emerging structural insights into transient receptor potential channel regulation by calmodulin.The Journal of physiology · 2026Review
- Small molecule inhibition rescues the skeletal dysplasia phenotype of Trpv4 mutant mice.JCI insight · 2026Article
- Calmodulin binding is required for calcium mediated TRPA1 desensitization.Nature communications · 2025Article
- Recent advances on the structure and the function relationships of the TRPV4 ion channel.Channels (Austin, Tex.) · 2024Review
- TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury.American journal of respiratory cell and molecular biology · 2024Article
- Compressive Myelopathy Secondary toJournal of pediatric genetics · 2024Article
- TRPV4-dependent CaBiophysical journal · 2024Article
- Structure of human TRPV4 in complex with GTPase RhoA.Nature communications · 2023Article
- Review
- Lighting up Nobel Prize-winning studies with protein intrinsic disorder.Cellular and molecular life sciences : CMLS · 2022Review
- Multiubiquitination of TRPV4 reduces channel activity independent of surface localization.The Journal of biological chemistry · 2022Article
- Ligand-Binding Sites in Vanilloid-Subtype TRP Channels.Frontiers in pharmacology · 2022Review
- Cross-talk between the calcium channel TRPV4 and reactive oxygen species interlocks adhesive and degradative functions of invadosomes.The Journal of cell biology · 2021Article
- Modulating the Mechanical Activation of TRPV4 at the Cell-Substrate Interface.Frontiers in bioengineering and biotechnology · 2020Article
- The Crossroad of Ion Channels and Calmodulin in Disease.International journal of molecular sciences · 2019Review
- CaInternational journal of molecular sciences · 2018Review
- Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A-mediated phosphorylation.The Journal of biological chemistry · 2018Article
- Identification of a Novel EF-Loop in the N-terminus of TRPM2 Channel Involved in Calcium Sensitivity.Frontiers in pharmacology · 2018Article
- When size matters: transient receptor potential vanilloid 4 channel as a volume-sensor rather than an osmo-sensor.The Journal of physiology · 2017Article
- Calmodulin is responsible for CaScientific reports · 2017Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.