{"doi":"10.1085/jgp.202313358","title":"IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels","abstract":"Pressure-dependent chronotropy of murine lymphatic collecting vessels relies on the activation of the Ca2+-activated chloride channel encoded by Anoctamin 1 (Ano1) in lymphatic muscle cells. Genetic ablation or pharmacological inhibition of ANO1 results in a significant reduction in basal contraction frequency and essentially complete loss of pressure-dependent frequency modulation by decreasing the rate of the diastolic depolarization phase of the ionic pacemaker in lymphatic muscle cells (LMCs). Oscillating Ca2+ release from sarcoendoplasmic reticulum Ca2+ channels has been hypothesized to drive ANO1 activity during diastole, but the source of Ca2+ for ANO1 activation in smooth muscle remains unclear. Here, we investigated the role of the inositol triphosphate receptor 1 (Itpr1; Ip3r1) in this process using pressure myography, Ca2+ imaging, and membrane potential recordings in LMCs of ex vivo pressurized inguinal-axillary lymphatic vessels from control or Myh11CreERT2;Ip3r1fl/fl (Ip3r1ismKO) mice. Ip3r1ismKO vessels had significant reductions in contraction frequency and tone but an increased contraction amplitude. Membrane potential recordings from LMCs of Ip3r1ismKO vessels revealed a depressed diastolic depolarization rate and an elongation of the plateau phase of the action potential (AP). Ca2+ imaging of LMCs using the genetically encoded Ca2+ sensor GCaMP6f demonstrated an elongation of the Ca2+ flash associated with an AP-driven contraction. Critically, diastolic subcellular Ca2+ transients were absent in LMCs of Ip3r1ismKO mice, demonstrating the necessity of IP3R1 activity in controlling ANO1-mediated diastolic depolarization. These findings indicate a critical role for IP3R1 in lymphatic vessel pressure-dependent chronotropy and contractile regulation.","journal":"The Journal of General Physiology","year":2023,"id":334112,"datarank":0.47032413238937254,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.0,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"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":1062465,"name":"G. Pea","orcid":"0009-0006-1412-4778","position":1,"is_corresponding":false},{"id":1062466,"name":"Sarah E Broyhill","orcid":"0000-0003-2627-3368","position":2,"is_corresponding":false},{"id":1062467,"name":"Advaya Patro","orcid":"0009-0006-3231-1753","position":3,"is_corresponding":false},{"id":854248,"name":"Karen H. Bromert","orcid":"0009-0008-0896-8581","position":4,"is_corresponding":false},{"id":1062468,"name":"Min Li","orcid":"0009-0001-6648-375X","position":5,"is_corresponding":false},{"id":532178,"name":"Charles E. Norton","orcid":"0000-0001-9442-4039","position":6,"is_corresponding":false},{"id":322912,"name":"Jorge A. Castorena‐Gonzalez","orcid":"0000-0001-5252-375X","position":7,"is_corresponding":false},{"id":772726,"name":"Edward J. Hancock","orcid":"0000-0003-1606-9611","position":8,"is_corresponding":false},{"id":361742,"name":"Christopher Bertram","orcid":"0009-0005-1575-4504","position":9,"is_corresponding":false},{"id":322913,"name":"Michael J. Davis","orcid":"0000-0002-7992-9300","position":10,"is_corresponding":false},{"id":322911,"name":"Scott D. Zawieja","orcid":"0000-0003-4658-3179","position":0,"is_corresponding":true}],"reference_count":132,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:48.843291Z","pmid":"37851027","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":[]}