{"doi":"10.1016/j.jbc.2021.100832","title":"Navigating the intricacies of cellular machinery","abstract":"Voltage-gated sodium channels (NaVs) underlie the initiation of action potentials in various excitable cell types and are regulated by channel-interacting proteins, including the cellular calcium sensor calmodulin and fibroblast growth factor homologous factors. Both of these are known to bind the NaV cytosolic C-terminal domain and modulate the channel’s electrophysiology, but it was unknown whether they had any allosteric interactions with each other. A recent rigorous study provides insights into the molecular interactions of these ion channels and their partners that crucially take the cellular landscape into consideration. Voltage-gated sodium channels (NaVs) underlie the initiation of action potentials in various excitable cell types and are regulated by channel-interacting proteins, including the cellular calcium sensor calmodulin and fibroblast growth factor homologous factors. Both of these are known to bind the NaV cytosolic C-terminal domain and modulate the channel’s electrophysiology, but it was unknown whether they had any allosteric interactions with each other. A recent rigorous study provides insights into the molecular interactions of these ion channels and their partners that crucially take the cellular landscape into consideration. The critical role of voltage-gated sodium channels (NaVs) in cell excitation makes the intricacies of channel modulation of acute consequence, as evidenced by diseases including epilepsy, cardiac arrhythmias, and chronic pain among others that result from NaV dysregulation (1Nathan S. Gabelli S.B. Yoder J.B. Srinivasan L. Aldrich R.W. Tomaselli G.F. Ben-Johny M. Amzel L.M. Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation.J. Gen. Physiol. 2021; 153e202012722Crossref PubMed Scopus (6) Google Scholar). NaVs cycle rapidly between closed, open, and inactivated states, with channel-interacting proteins fine-tuning the transition between these functional states. Binding of fibroblast growth factor homologous factors (FGFs 11-14) has been associated with an increased rate of voltage-dependent fast inactivation as well as long-term inactivation, parameters that determine how quickly the inward sodium current is quelled and how long the channel is inactivated before it is able to open again, respectively (2Dover K. Solinas S. D'Angelo E. Goldfarb M. Long-term inactivation particle for voltage-gated sodium channels.J. Physiol. 2010; 588: 3695-3711Crossref PubMed Scopus (55) Google Scholar). In parallel, CaM binds two Ca2+ on each of its two lobes and has been shown to interact with a highly conserved ‘IQ’ motif in the NaV C-terminal domain (CTD) in both its calcium ion–free (apo-) calmodulin (CaM) and (Ca2+)4–CaM states. The functional consequence of the interaction between CaM and the NaV CTD is dynamic and dependent on both the NaV isoform and calcium status of CaM, with calcium-dependent channel inactivation being the best characterized (in skeletal muscle isoform NaV1.4 in particular; (3Ben-Johny M. Yang P.S. Niu J. Yang W. Joshi-Mukherjee R. Yue D.T. Conservation of Ca2+/calmodulin regulation across Na and Ca2+ channels.Cell. 2014; 157: 1657-1670Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 4Yoder J.B. Ben-Johny M. Farinelli F. Srinivasan L. Shoemaker S.R. Tomaselli G.F. Gabelli S.B. Amzel L.M. Ca(2+)-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif.Nat. Commun. 2019; 10: 1514Crossref PubMed Scopus (20) Google Scholar, 5Lou J.Y. Laezza F. Gerber B.R. Xiao M. Yamada K.A. Hartmann H. Craig A.M. Nerbonne J.M. Ornitz D.M. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels.J. Physiol. 2005; 569: 179-193Crossref PubMed Scopus (134) Google Scholar)). Although CaM and FGFs are known to interact with adjacent regions of the Nav CTD, it was unknown whether CaM and FGFs interacted with each other as well, or whether they independently interfaced with the channel. Although an indir","journal":"Journal of Biological Chemistry","year":2021,"id":211878,"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":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":434249,"name":"Sandra B. Gabelli","orcid":"0000-0003-1205-5204","position":1,"is_corresponding":false},{"id":286187,"name":"Sara Nathan","orcid":"0000-0002-0090-0303","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:52:23.670339Z","pmid":"34048713","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":[]}