Year: 2023
Type: article
Abstract: Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.
Source: Nature Communications
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: National Science Foundation, U.S. Department of Energy, U.S. Department of Health and Human Services, Muscular Dystrophy Association, Oregon Health and Science University, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Division of Electrical, Communications and Cyber Systems, Biological and Environmental Research
Awards: NNCI: North Carolina Research Triangle Nanotechnology Network (RTNN), G1676019983, Structure, function, and pharmacology of neuronal membrane transport proteins, G192318385, G3042889476, G3144446506, G3264053397, G3275407028, G3508161151, G4429615956, Pathogenesis of TRPV4-related peripheral neuropathy, G5718375046, Pacific Northwest Center for Cryo-EM, G5973914729, G6221506569, G6780141363, G6810723037, G7212041399, G7562546725, G7673727097, G7913850483, G9000060489, G9000070529, G9000143683
OpenAlex ID: W4381801298