Interdomain Interactions Control Ca2+-Dependent Potentiation in the Cation Channel TRPV4

• Published in: PloS one Vol. 5; no. 5; p. e10580
• Main Authors: Strotmann, Rainer, Semtner, Marcus, Kepura, Frauke, Plant, Tim D., Schöneberg, Torsten
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.05.2010; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Binding Sites; Biochemistry/Cell Signaling and Trafficking Structures; Biological Assay; Calcium (intracellular); Calcium - pharmacology; Calcium channels; Calcium ions; Calcium permeability; Calcium-binding protein; Calmodulin; Calmodulin - metabolism; Cations; Cell Biology/Cell Signaling; Cell Line; Channels; Experiments; Homology; Humans; Intracellular; Ion Channel Gating - drug effects; Localization; Molecular Sequence Data; Mutation - genetics; Peptides; Peptides - metabolism; Permeability; Physiology/Cell Signaling; Potentiation; Protein Binding - drug effects; Protein Multimerization - drug effects; Protein Structure, Tertiary; Structure-Activity Relationship; TRPV Cation Channels - chemistry; TRPV Cation Channels - metabolism; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010580

Several Ca(2+)-permeable channels, including the non-selective cation channel TRPV4, are subject to Ca(2+)-dependent facilitation. Although it has been clearly demonstrated in functional experiments that calmodulin (CaM) binding to intracellular domains of TRP channels is involved in this process, the molecular mechanism remains elusive. In this study, we provide experimental evidence for a comprehensive molecular model that explains Ca(2+)-dependent facilitation of TRPV4. In the resting state, an intracellular domain from the channel N terminus forms an autoinhibitory complex with a C-terminal domain that includes a high-affinity CaM binding site. CaM binding, secondary to rises in intracellular Ca(2+), displaces the N-terminal domain which may then form a homologous interaction with an identical domain from a second subunit. This represents a novel potentiation mechanism that may also be relevant in other Ca(2+)-permeable channels.