{"doi":"10.1111/1440-1681.12593","title":"Pharmacological rescue of <scp>hERG</scp> currents carried out by G604S and wide type <scp>hERG</scp> co‐expression","abstract":"<jats:title>Summary</jats:title><jats:p>Mutations in <jats:italic>human ether‐a‐go‐go‐related gene</jats:italic> (<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>) can lead to type 2 long‐<jats:styled-content style=\"fixed-case\">QT</jats:styled-content> syndrome (<jats:styled-content style=\"fixed-case\">LQT</jats:styled-content>2). The authors previously identified the <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> mutation G604S results in a loss of function and obviously decreased current amplitude and impaired channel protein trafficking when co‐expressed with <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>. The present study further investigates the biological and electrophysiological consequences of pharmacologic chaperones in <jats:styled-content style=\"fixed-case\">HEK</jats:styled-content>293 cells expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> or co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>. It was found that a low temperature (27°C), thapsigargin, <jats:styled-content style=\"fixed-case\">NS</jats:styled-content>1643 and E‐4031 fail to rescue the G604S mutation. Interestingly, only E‐4031 treatment resulted in a significant increase in <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> currents in cells co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>, correspondingly more mature protein band at 155 kDa by Western blotting and an increased membrane staining by confocal microscopy. In addition, E‐4031 treatment shifted the steady‐state half maximal activation voltage (<jats:italic>V</jats:italic><jats:sub>1/2</jats:sub>) of the inactivation curve by +8 mV in cells co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>. The present experimental results suggest that a G604S mutation is resistant to pharmacological rescue. E‐4031 treatment resulted in a significant increase in <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> currents by promoting the <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> channel processing and trafficking in cells co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and WT‐hERG.</jats:p>","journal":"Clinical and Experimental Pharmacology and Physiology","year":2016,"id":635656,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"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":364817,"name":"Aifeng Zhang","orcid":"0000-0003-4124-2199","position":1,"is_corresponding":false},{"id":417655,"name":"Xueyan Guo","orcid":"0000-0003-0119-1585","position":2,"is_corresponding":false},{"id":1649253,"name":"Hua Qiang","orcid":null,"position":3,"is_corresponding":false},{"id":835970,"name":"Ping Liu","orcid":"0000-0001-8363-070X","position":4,"is_corresponding":false},{"id":239021,"name":"Ling Bai","orcid":null,"position":5,"is_corresponding":false},{"id":1426678,"name":"Aiqun Ma","orcid":"0000-0002-2527-8688","position":6,"is_corresponding":false},{"id":1649246,"name":"Jianhua Huo","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Pharmacological rescue of <scp>hERG</scp> currents carried out by G604S and wide type <scp>hERG</scp> co‐expression","abstract":"<jats:title>Summary</jats:title><jats:p>Mutations in <jats:italic>human ether‐a‐go‐go‐related gene</jats:italic> (<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>) can lead to type 2 long‐<jats:styled-content style=\"fixed-case\">QT</jats:styled-content> syndrome (<jats:styled-content style=\"fixed-case\">LQT</jats:styled-content>2). The authors previously identified the <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> mutation G604S results in a loss of function and obviously decreased current amplitude and impaired channel protein trafficking when co‐expressed with <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>. The present study further investigates the biological and electrophysiological consequences of pharmacologic chaperones in <jats:styled-content style=\"fixed-case\">HEK</jats:styled-content>293 cells expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> or co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>. It was found that a low temperature (27°C), thapsigargin, <jats:styled-content style=\"fixed-case\">NS</jats:styled-content>1643 and E‐4031 fail to rescue the G604S mutation. Interestingly, only E‐4031 treatment resulted in a significant increase in <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> currents in cells co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>, correspondingly more mature protein band at 155 kDa by Western blotting and an increased membrane staining by confocal microscopy. In addition, E‐4031 treatment shifted the steady‐state half maximal activation voltage (<jats:italic>V</jats:italic><jats:sub>1/2</jats:sub>) of the inactivation curve by +8 mV in cells co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content>. The present experimental results suggest that a G604S mutation is resistant to pharmacological rescue. E‐4031 treatment resulted in a significant increase in <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> currents by promoting the <jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> channel processing and trafficking in cells co‐expressing G604S‐<jats:styled-content style=\"fixed-case\">hERG</jats:styled-content> and WT‐hERG.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27199074","pmcid":null,"openalex_id":null,"authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2F1440-1681.12593","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/1440-1681.12593","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":["Humans","Cresols","Phenylurea Compounds","Piperidines","Pyridines","Amino Acid Substitution","Temperature","Ion Channel Gating","Gene Expression","Mutation","Ether-A-Go-Go Potassium Channels","Electrophysiological Phenomena","HEK293 Cells"],"keywords":["Patch-clamp","Long QT syndrome","G604s","Herg Mutation"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T15:24:53.801731Z","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":[]}