{"doi":"10.3390/life15091345","title":"FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function","abstract":"Voltage-gated Na+ channels (Nav) are the molecular determinants of action potential initiation and propagation. Among the nine voltage-gated Na+ channel isoforms (Nav1.1–Nav1.9), Nav1.2 and Nav1.6 are of particular interest because of their developmental expression profile throughout the central nervous system (CNS) and their association with channelopathies. Although the α-subunit coded by each of the nine isoforms can sufficiently confer transient Na+ currents (INa), in vivo these channels are modulated by auxiliary proteins like intracellular fibroblast growth factor (iFGFs) through protein–protein interaction (PPI), and probes developed from iFGF/Nav PPI complexes have been shown to precisely modulate Nav channels. Previous studies identified ZL0177, a peptidomimetic derived from a short peptide sequence at the FGF14/Nav1.6 PPI interface, as a functional modulator of Nav1.6-mediated INa+. However, the isoform specificity, binding sites, and putative physiological impact of ZL0177 on neuronal excitability remain unexplored. Here, we used automated planar patch-clamp electrophysiology to assess ZL0177’s functional activity in cells stably expressing Nav1.2 or Nav1.6. While ZL0177 was found to suppress INa in both Nav1.2- and Nav1.6-expressing cells, ZL0177 elicited functionally divergent effects on channel kinetics that were isoform-specific and supported by differential docking of the compound to AlphaFold structures of the two channel isoforms. Computational modeling predicts that ZL0177 modulates Nav1.2 and Nav1.6 in an isoform-specific manner, eliciting phenotypically divergent effects on action potential discharge. Taken together, these results highlight the potential of PPI derivatives for isoform-specific regulation of Nav channels and the development of therapeutics for channelopathies.","journal":"Life","year":2025,"id":546395,"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":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1121716,"name":"Zahra Haghighijoo","orcid":"0000-0001-5119-1028","position":1,"is_corresponding":false},{"id":1221807,"name":"Carmen Alina Lupaşcu","orcid":"0000-0002-7870-5620","position":2,"is_corresponding":false},{"id":381780,"name":"A.K. Singh","orcid":"0000-0001-7549-8163","position":3,"is_corresponding":false},{"id":1122127,"name":"Nana A. Goode","orcid":null,"position":4,"is_corresponding":false},{"id":737593,"name":"Timothy J. Baumgartner","orcid":"0000-0002-0330-577X","position":5,"is_corresponding":false},{"id":778911,"name":"Jully Singh","orcid":null,"position":6,"is_corresponding":false},{"id":1438110,"name":"Yu Xue","orcid":"0009-0001-6625-704X","position":7,"is_corresponding":false},{"id":383917,"name":"Pingyuan Wang","orcid":"0009-0005-0368-5070","position":8,"is_corresponding":false},{"id":383918,"name":"Haiying Chen","orcid":"0000-0003-2841-5518","position":9,"is_corresponding":false},{"id":506280,"name":"Dinler A. Antunes","orcid":"0000-0001-7947-6455","position":10,"is_corresponding":false},{"id":738224,"name":"Marijn Lijffijt","orcid":"0000-0001-5760-1729","position":11,"is_corresponding":false},{"id":107272,"name":"Jia Zhou","orcid":"0000-0002-2811-1090","position":12,"is_corresponding":false},{"id":290700,"name":"Michele Migliore","orcid":"0000-0002-7584-6292","position":13,"is_corresponding":false},{"id":381782,"name":"Fernanda Laezza","orcid":"0000-0003-1141-1852","position":14,"is_corresponding":false},{"id":872643,"name":"Parsa Arman","orcid":"0009-0000-3787-5474","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:53:32.285899Z","pmid":"41010287","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":[]}