{"doi":"10.7554/elife.89465.1.sa4","title":"Author Response: Mechanical activation of TWIK-related potassium channel by nanoscopic movement and rapid second messenger signaling","abstract":"Rapid transduction of force into a biological signal allows living cells to respond to mechanical changes in their environment. Force is thought to first act on the plasma membrane and alter membrane associated proteins. The enzyme phospholipase D2 (PLD2) is mechanosensitive and associates with the membrane through a covalently attached palmitate lipid (palmitoylation) and its affinity for a structured membrane-lipid site comprised of cholesterol and saturated ganglioside (GM1). Here we show stretch activation of TWIK-related K+ channel (TREK-1) is mechanically activated by movement from ordered GM1 clusters to 4,5-bisphosphate (PIP2) clusters. First, force (shear or stretch) deforms the ordered GM1 lipids and lowers cholesterol in the membrane. Second the deformation disrupts the interaction of palmitate with the ordered GM1 lipids allowing a complex of TREK-1 and PLD2 to move to PIP2 clusters where the enzyme produces the second messenger phosphatidic acid (PA) that helps gate the channel. Co-expression of catalytically dead PLD2, devoid of PA production, inhibits TREK-1 stretch currents in the cell membrane. Loading cultured cells with cholesterol clusters TREK-1 with GM1 lipids and inhibits the channel and depletion of cholesterol in astrocytes moves TREK-1 away from GM1. Reduction or elimination of PLD2 expression in flies results in hypersensitivity to mechanical force—decreased thresholds. We conclude the ordered lipids sense force and PLD2 combines with TREK-1 to elicit a mechanical response. The hypersensitivity of PLD2 deficient flies suggests an in vivo role for PA lipid signaling in setting mechanosensitivity and pain thresholds.Shear thinning activates TREK-1 through a second messenger.","journal":null,"year":2023,"id":409843,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245304,"name":"Mahmud Arif Pavel","orcid":"0000-0002-2709-8744","position":1,"is_corresponding":false},{"id":1116608,"name":"Samuel S. Hansen","orcid":null,"position":2,"is_corresponding":false},{"id":1116609,"name":"Manasa V. Gudheti","orcid":null,"position":3,"is_corresponding":false},{"id":1189713,"name":"Hao Wang","orcid":"0000-0003-1862-8229","position":4,"is_corresponding":false},{"id":550193,"name":"Zixuan Yuan","orcid":"0000-0003-0665-5086","position":5,"is_corresponding":false},{"id":688552,"name":"Keith R. Murphy","orcid":null,"position":6,"is_corresponding":false},{"id":263760,"name":"William W. Ja","orcid":"0000-0002-4003-7356","position":7,"is_corresponding":false},{"id":551951,"name":"Heather A. Ferris","orcid":"0000-0002-6321-3447","position":8,"is_corresponding":false},{"id":463421,"name":"Erik M. Jørgensen","orcid":"0000-0002-2978-8028","position":9,"is_corresponding":false},{"id":245307,"name":"Scott B. Hansen","orcid":"0000-0003-0086-9753","position":10,"is_corresponding":false},{"id":245305,"name":"Erling N. Petersen","orcid":"0000-0002-3243-9611","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:21:31.144858Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}