{"doi":"10.1083/jcb.202107120","title":"TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1","abstract":"<jats:p>TRPC3, a member of the transient receptor potential (TRP) superfamily of cation channels, is a lipid-regulated, Ca2+-permeable channel that mediates essential components of the receptor evoked Ca2+ signal. The modes and mechanisms by which lipids regulate TRPC3 and other members of the TRPC channel family are not well understood. Here, we report that PI(4,5)P2 regulates TRPC3 in three independent modes. PLC-dependent hydrolysis generates diacylglycerol (DAG) that interacts with lipid-binding site 2 in the channel pore. PI(4,5)P2 interacts with lipid site 1 to inhibit TRPC3 opening and regulate access of DAG to the pore lipid site 2. PI(4,5)P2 is required for regulating pore ionic selectivity by receptor stimulation. Notably, the activation and regulation of TRPC3 by PI(4,5)P2 require recruitment of TRPC3 to the ER/PM junctions at a PI(4,5)P2-rich domain. Accordingly, we identified an FFAT site at the TRPC3 N-terminal loop within the linker helices that envelope the C-terminus pole helix. The FFAT site interacts with the ER-resident VAPB to recruit TRPC3 to the ER/PM junctions and control its receptor-mediated activation. The TRPC3’s lipid interacting sites are fully conserved in TRPC6 and TRPC7 and in part in other TRPC channels. These findings inform on multiple modes of regulation of ion channels by lipids that may be relevant to diseases affected by aberrant TRPC channel functions.</jats:p>","journal":"Journal of Cell Biology","year":2022,"id":26431,"datarank":0.9349864136627333,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"self_citation_contribution":0.5289540786924243,"citation_network_contribution":0.40603233497030905,"self_endowment_contribution":0.5289540786924243,"citer_contribution":0.40603233497030905,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":27,"citers_with_citation_signal":21,"citers_with_endowment":21,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":152927,"name":"Wei-Yin Lin","orcid":null,"position":1,"is_corresponding":false},{"id":152928,"name":"Spencer R. Leibow","orcid":"0000-0001-7781-7463","position":2,"is_corresponding":false},{"id":152929,"name":"Alexander J. Morateck","orcid":"0000-0001-5312-9885","position":3,"is_corresponding":false},{"id":152930,"name":"Malini Ahuja","orcid":null,"position":4,"is_corresponding":false},{"id":147712,"name":"Shmuel Muallem","orcid":"0000-0002-6189-4947","position":5,"is_corresponding":false},{"id":152926,"name":"Haiping Liu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35416932","pmcid":"PMC9011324","openalex_id":"https://openalex.org/W4223502152","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"NIH/NIDCR DE000735-10","title":null},{"funder_name":"National Institutes of Health","grant_id":"1ZIADE000735-10","title":"Ca2+ signaling and HCO3- secretion by exocrine glands"}],"total_grants":2,"fwci":3.9141,"citation_percentile":0.94925325,"influential_citations":2,"citation_trend":[{"year":2022,"count":7},{"year":2023,"count":6},{"year":2024,"count":9},{"year":2025,"count":9},{"year":2026,"count":2}],"oa_status":"bronze","license":"CC BY NC SA","oa_locations":[{"url":"https://rupress.org/jcb/article-pdf/221/5/e202107120/1431524/jcb_202107120.pdf","host_type":"journal"},{"url":"https://rupress.org/jcb/article-pdf/221/5/e202107120/1431524/jcb_202107120.pdf","host_type":"HYBRID"},{"url":"https://rupress.org/jcb/article-pdf/221/5/e202107120/1431524/jcb_202107120.pdf","host_type":"publisher"},{"url":"https://rupress.org/jcb/article-pdf/doi/10.1083/jcb.202107120/1828961/jcb_202107120.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1083/jcb.202107120","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35416932","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9011324","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9011324","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9011324?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1083/jcb.202107120","host_type":""}],"fields_of_study":["Ion Channels and Receptors","Phytochemicals and Antioxidant Activities","Postharvest Quality and Shelf Life Management","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Binding Sites","Calcium","Calcium Channels","Cell Membrane","Endoplasmic Reticulum","Phosphatidylinositol 4,5-Diphosphate","Stromal Interaction Molecule 1","TRPC Cation Channels"],"mesh_terms":["Stromal Interaction Molecule 1","Binding Sites","Calcium","Cell Membrane","Endoplasmic Reticulum","Calcium Channels","Phosphatidylinositol 4,5-Diphosphate","TRPC Cation Channels"],"keywords":["TRPC3","TRPC","Transient receptor potential channel","Diacylglycerol kinase","TRPC5","TRPC1","Cell biology","Biology","Gating","TRPC6","Biophysics","Ion channel","Biochemistry","Receptor","Signal transduction","Protein kinase C","Phosphatidylinositol 4,5-Diphosphate","Binding Sites","Cell Membrane","Calcium","Calcium Channels","Stromal Interaction Molecule 1","Endoplasmic Reticulum","Article","TRPC Cation Channels"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-08T14:14:20.500400Z","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":[]}