{"doi":"10.7554/elife.15202","title":"Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels","abstract":"<jats:p>Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state-dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels.</jats:p>","journal":"eLife","year":2016,"id":683582,"datarank":0.635115975689589,"base_score":4.23410650459726,"endowment":4.23410650459726,"self_citation_contribution":0.635115975689589,"citation_network_contribution":0.0,"self_endowment_contribution":0.635115975689589,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":68,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":1785767,"name":"Elaine Reichert","orcid":null,"position":1,"is_corresponding":false},{"id":253698,"name":"Adam E. 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Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels.</jats:p>","is_dataset_classified":null,"base_score":4.23410650459726,"endowment":4.23410650459726,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27215841","pmcid":null,"openalex_id":"https://openalex.org/W2400555916","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"1-R01-EB012498","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01EB012498-03","title":"Engineering Microbial Rhodopsins as Optical Voltage Sensors"},{"funder_name":"NIBIB NIH HHS","grant_id":"R01 EB012498","title":null},{"funder_name":"Howard Hughes Medical Institute","grant_id":"","title":null}],"total_grants":4,"fwci":3.524,"citation_percentile":0.92988519,"influential_citations":0,"citation_trend":[{"year":2016,"count":1},{"year":2017,"count":10},{"year":2018,"count":6},{"year":2019,"count":5},{"year":2020,"count":12},{"year":2021,"count":11},{"year":2022,"count":11},{"year":2023,"count":7},{"year":2024,"count":4},{"year":2025,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.7554/elife.15202","host_type":"journal"},{"url":"https://doi.org/10.7554/elife.15202","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/articles/15202/elife-15202-v2.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/articles/15202/elife-15202-v2.xml","host_type":"publisher"},{"url":"https://elifesciences.org/articles/15202","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27215841","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4907688","host_type":"repository"},{"url":"http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662245","host_type":"repository"},{"url":"https://doaj.org/article/91baae5f66ac4873b3b3406abc936764","host_type":"repository"},{"url":"http://dx.doi.org/10.7554/eLife.15202","host_type":""},{"url":"https://dx.doi.org/10.7554/elife.15202","host_type":""},{"url":"https://doi.org/https://doi.org/10.7554/eLife.15202","host_type":""}],"fields_of_study":["Ion channel regulation and function","Receptor Mechanisms and Signaling","Nicotinic Acetylcholine Receptors Study","0301 basic medicine","03 medical and health sciences","0303 health sciences","Action Potentials","Electrophysiology","Gene Expression","Genes, Reporter","Green Fluorescent Proteins","HEK293 Cells","High-Throughput Screening Assays","Humans","Ion Channel Gating","Kinetics","Luminescent Proteins","NAV1.7 Voltage-Gated Sodium Channel","Optical Devices","Potassium Channels, Inwardly Rectifying","Small Molecule Libraries","Sodium Channel Blockers","Spectrometry, Fluorescence","Transgenes"],"mesh_terms":["Action Potentials","Electrophysiology","Humans","Kinetics","Luminescent Proteins","Spectrometry, Fluorescence","Ion Channel Gating","Gene Expression","Genes, Reporter","Transgenes","Potassium Channels, Inwardly Rectifying","Sodium Channel Blockers","Green Fluorescent Proteins","Small Molecule Libraries","Optical Devices","High-Throughput Screening Assays","HEK293 Cells","NAV1.7 Voltage-Gated Sodium Channel"],"keywords":["Electrophysiology","Ion channel","Voltage clamp","Depolarization","Patch clamp","Biophysics","Neuroscience","Voltage-gated ion channel","Chemistry","Biology","Receptor","Biochemistry","QH301-705.5","Science","Green Fluorescent Proteins","610","Action Potentials","Gene Expression","Small Molecule Libraries","Genes, Reporter","None","Humans","Transgenes","Biology (General)","Potassium Channels, Inwardly Rectifying","optogenetics","Q","NAV1.7 Voltage-Gated Sodium Channel","R","ion channels","Optical Devices","Biophysics and Structural Biology","High-Throughput Screening Assays","Kinetics","Luminescent Proteins","HEK293 Cells","Spectrometry, Fluorescence","Medicine","Ion Channel Gating","high throughput screening","Sodium Channel Blockers","structural biology"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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