Unconventional interactions of the TRPV4 ion channel with beta-adrenergic receptor ligands

The transient receptor potential vanilloid 4 (TRPV4) ion channel is present in different tissues including those of the airways. This channel is activated in response to stimuli such as changes in temperature, hypoosmotic conditions, mechanical stress, and chemicals from plants, lipids, and others. TRPV4's overactivity and/or dysfunction has been associated with several diseases, such as skeletal dysplasias, neuromuscular disorders, and lung pathologies such as asthma and cardiogenic lung edema and COVID-19-related respiratory malfunction. TRPV4 antagonists and blockers have been described; nonetheless, the mechanisms involved in achieving inhibition of the channel remain scarce, and the search for safe use of these molecules in humans continues. Here, we show that the widely used bronchodilator salbutamol and other ligands of β-adrenergic receptors inhibit TRPV4's activation. We also demonstrate that inhibition of TRPV4 by salbutamol is achieved through interaction with two residues located in the outer region of the pore and that salbutamol leads to channel closing, consistent with an allosteric mechanism. Our study provides molecular insights into the mechanisms that regulate the activity of this physiopathologically important ion channel.