{"doi":"10.1085/jgp.202012760","title":"Dynein regulates Kv7.4 channel trafficking from the cell membrane","abstract":"The dynein motor protein transports proteins away from the cell membrane along the microtubule network. Recently, we found the microtubule network was important for regulating the membrane abundance of voltage-gated Kv7.4 potassium channels in vascular smooth muscle. Here, we aimed to investigate the influence of dynein on the microtubule-dependent internalization of the Kv7.4 channel. Patch-clamp recordings from HEK293B cells showed Kv7.4 currents were increased after inhibiting dynein function with ciliobrevin D or by coexpressing p50/dynamitin, which specifically interferes with dynein motor function. Mutation of a dynein-binding site in the Kv7.4 C terminus increased the Kv7.4 current and prevented p50 interference. Structured illumination microscopy, proximity ligation assays, and coimmunoprecipitation showed colocalization of Kv7.4 and dynein in mesenteric artery myocytes. Ciliobrevin D enhanced mesenteric artery relaxation to activators of Kv7.2-Kv7.5 channels and increased membrane abundance of Kv7.4 protein in isolated smooth muscle cells and HEK293B cells. Ciliobrevin D failed to enhance the negligible S-1-mediated relaxations after morpholino-mediated knockdown of Kv7.4. Mass spectrometry revealed an interaction of dynein with caveolin-1, confirmed using proximity ligation and coimmunoprecipitation assays, which also provided evidence for interaction of caveolin-1 with Kv7.4, confirming that Kv7.4 channels are localized to caveolae in mesenteric artery myocytes. Lastly, cholesterol depletion reduced the interaction of Kv7.4 with caveolin-1 and dynein while increasing the overall membrane expression of Kv7.4, although it attenuated the Kv7.4 current in oocytes and interfered with the action of ciliobrevin D and channel activators in arterial segments. Overall, this study shows that dynein can traffic Kv7.4 channels in vascular smooth muscle in a mechanism dependent on cholesterol-rich caveolae.","journal":"The Journal of General Physiology","year":2021,"id":186593,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":713147,"name":"Salomé Rognant","orcid":"0000-0003-3276-5887","position":1,"is_corresponding":false},{"id":350953,"name":"Geoffrey W. Abbott","orcid":"0000-0003-4552-496X","position":2,"is_corresponding":false},{"id":246755,"name":"Lijo Cherian Ozhathil","orcid":"0000-0002-4620-8507","position":3,"is_corresponding":false},{"id":744796,"name":"Per Hägglund","orcid":"0000-0002-6627-7518","position":4,"is_corresponding":false},{"id":420740,"name":"Vincenzo Barrese","orcid":"0000-0001-8721-8843","position":5,"is_corresponding":false},{"id":744797,"name":"Christine Y. Chuang","orcid":"0000-0001-6144-632X","position":6,"is_corresponding":false},{"id":628245,"name":"Thomas Jespersen","orcid":"0000-0001-6575-360X","position":7,"is_corresponding":false},{"id":578673,"name":"Michael J. Davies","orcid":"0000-0002-5196-6919","position":8,"is_corresponding":false},{"id":668433,"name":"Iain A. Greenwood","orcid":"0000-0002-0603-0492","position":9,"is_corresponding":false},{"id":345802,"name":"Pontus Gourdon","orcid":"0000-0002-8631-3539","position":10,"is_corresponding":false},{"id":445109,"name":"Christian Aalkjær","orcid":"0000-0003-2618-4015","position":11,"is_corresponding":false},{"id":475433,"name":"Thomas A. Jepps","orcid":"0000-0002-9903-714X","position":12,"is_corresponding":false},{"id":475431,"name":"Jennifer van der Horst","orcid":"0000-0002-0167-8943","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-18T23:48:46.850806Z","pmid":"33533890","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":[]}