Open-channel block of human TRPV6 by polyamine spermine
Year: 2026
Type: article
Abstract: Polyamines are organic cations that are present at sub-millimolar concentrations in the cytoplasm and extracellular fluids and serve as versatile modulators of TRP channels, fine-tuning their functions in physiological and pathological contexts, including pain, inflammation and cancer. Despite extensive functional studies, the structural basis by which polyamines regulate TRP channels remains unclear. Here, we combine calcium imaging, electrophysiology, cryo-electron microscopy, mutagenesis and molecular dynamics simulations to study regulation of human TRPV6 by polyamine spermine. Our functional experiments demonstrate voltage-dependent block of TRPV6-mediated currents by spermine. Cryo-electron microscopy reveals that spermine binds in the open pore of TRPV6, extending along the pore axis through the selectivity filter and central cavity. Mutagenesis and molecular dynamics simulations confirm the main binding site of spermine in the selectivity filter and suggest a stepwise molecular mechanism of channel block that includes two more binding sites in the pore transiently occupied by spermine. Our findings enrich the knowledge about TRPV6 regulation by endogenous factors and provide details of the ion channel blocking mechanism that can be explored for inhibition of this channel in disease conditions.
Source: Nature Communications
Institutions: Columbia University, Russian Academy of Sciences, InSysBio (Russia), Institute of Bioorganic Chemistry, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, German Center for Lung Research, National Research University Higher School of Economics, Columbia University Irving Medical Center
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Awards: G2390790659, G2775188920, Structure and Function of AMPA subtype ionotropic glutamate receptors, G5626970539, Pacific Northwest Center for Cryo-EM, G6216106575, G7986127690, Single-Particle Cryo-EM Characterization of AMPA Receptor Functional States, Structure and Function of Ionotropic Glutamate Receptors, Structure and function of Transient Receptor Potential Channels, Molecular mechanisms of polymodal TRP channels in regulation of microvascular endothelial function, Structural and functional principles of activation and regulation of the transient receptor potential channel TRPV3.
OpenAlex ID: W7162571969