{"doi":"10.1101/2022.03.04.482974","title":"A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels","abstract":"Abstract Resurgent currents ( I NaR ) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing, and contribute to neuronal hyperexcitability and disease pathophysiology. Here we show, for the first time, that I NaR can be reconstituted in a heterologous system by co-expression of sodium channel α-subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces I NaR from Nav1.8, Nav1.9 tetrodotoxin-resistant neuronal channels and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated I NaR . Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 I NaR . In nociceptive sensory neurons, FHF4A knockdown significantly reduces I NaR amplitude and the percentage of neurons that generate I NaR , substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant I NaR generation and provides important potential targets for pain treatment.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":306491,"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":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":830771,"name":"Jonathan W. Theile","orcid":null,"position":1,"is_corresponding":false},{"id":330370,"name":"Agnes Zybura","orcid":null,"position":2,"is_corresponding":false},{"id":395092,"name":"Yanling Pan","orcid":"0000-0002-0915-2639","position":3,"is_corresponding":false},{"id":1000558,"name":"Zhixin Lin","orcid":"0009-0009-4710-2024","position":4,"is_corresponding":false},{"id":276991,"name":"Theodore Cummins","orcid":"0000-0001-9509-6380","position":5,"is_corresponding":false},{"id":395093,"name":"Yucheng Xiao","orcid":"0000-0002-0298-7158","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T00:32:48.984902Z","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":[]}