{"doi":"10.1101/2020.04.13.039743","title":"Specific PIP <sub>2</sub> Binding Promotes Calcium Activation of TMEM16A Chloride Channels","abstract":"Abstract TMEM16A is a widely expressed Ca 2+ -activated Cl - channel that regulates crucial physiological functions including fluid secretion, neuronal excitability, and smooth muscle contraction. There is a critical need to understand the molecular mechanisms of TMEM16A gating and regulation. However, high-resolution TMEM16A structures have failed to reveal an activated state with unobstructed permeation pathway even with saturating Ca 2+ . This has been attributed to the requirement of PIP 2 for preventing TMEM16A desensitization. Here, we show that specific binding PIP 2 to TMEM16A can lead to spontaneous opening of the permeation pathway in the Ca 2+ -bound state. The predicted activated state is highly consistent with a wide range of mutagenesis and functional data. It yields a maximal Cl - conductance of ~1 pS, similar to experimental estimates, and recapitulates the selectivity of larger SCN - over Cl - . The resulting molecular mechanism of activation provides a basis for understanding the interplay of multiple signals in controlling TMEM16A channel function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126490,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":238225,"name":"Jianhan Chen","orcid":"0000-0002-5281-1150","position":1,"is_corresponding":false},{"id":573965,"name":"Zhiguang Jia","orcid":"0000-0002-9902-4832","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-18T23:15:23.509897Z","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":[]}