{"doi":"10.1113/jp279917","title":"A chloride channel blocker prevents the suppression by inorganic phosphate of the cytosolic calcium signals that control muscle contraction","abstract":"Key points Accumulation of inorganic phosphate (P i ) may contribute to muscle fatigue by precipitating calcium salts inside the sarcoplasmic reticulum (SR). Neither direct demonstration of this process nor definition of the entry pathway of P i into SR are fully established. We showed that P i promoted Ca 2+ release at concentrations below 10 m m and decreased it at higher concentrations. This decrease correlated well with that of [Ca 2+ ] SR . Pre‐treatment of permeabilized myofibres with 2 m m Cl − channel blocker 9‐anthracenecarboxylic acid (9AC) inhibited both effects of P i . The biphasic dependence of Ca 2+ release on [P i ] is explained by a direct effect of P i acting on the SR Ca 2+ release channel, combined with the intra‐SR precipitation of Ca 2+ salts. The effects of 9AC demonstrate that P i enters the SR via a Cl − pathway of an as‐yet‐undefined molecular nature. Abstract Fatiguing exercise causes hydrolysis of phosphocreatine, increasing the intracellular concentration of inorganic phosphate (P i ). P i diffuses into the sarcoplasmic reticulum (SR) where it is believed to form insoluble Ca 2+ salts, thus contributing to the impairment of Ca 2+ release. Information on the P i entrance pathway is still lacking. In amphibian muscles endowed with isoform 3 of the RyR channel, Ca 2+ spark frequency is correlated with the Ca 2+ load of the SR and can be used to monitor this variable. We studied the effects of P i on Ca 2+ sparks in permeabilized fibres of the frog. Relative event frequency ( f / f ref ) rose with increasing [P i ], reaching 2.54 ± 1.6 at 5 m m, and then decreased monotonically, reaching 0.09 ± 0.03 at [P i ] = 80 m m . Measurement of [Ca 2+ ] SR confirmed a decrease correlated with spark frequency at high [P i ]. A large [Ca 2+ ] SR surge was observed upon P i removal. Anion channels are a putative path for P i into the SR. We tested the effect of the chloride channel blocker 9‐anthracenecarboxylic acid (9AC) on P i entrance. 9AC (400 µ m) applied to the cytoplasm produced a non‐significant increase in spark frequency and reduced the P i effects on this parameter. Fibre treatment with 2 m m 9AC in the presence of high cytoplasmic Mg 2+ suppressed the effects of P i on [Ca 2+ ] SR and spark frequency up to 55 m m [P i ]. These results suggest that chloride channels (or transporters) provide the main pathway of inorganic ph","journal":"The Journal of Physiology","year":2020,"id":90344,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":455333,"name":"Germán Pequera","orcid":"0000-0002-2696-1630","position":1,"is_corresponding":false},{"id":455334,"name":"Bradley S. Launikonis","orcid":"0000-0003-0700-4867","position":2,"is_corresponding":false},{"id":455335,"name":"Eduardo Rı́os","orcid":"0000-0003-0985-8997","position":3,"is_corresponding":false},{"id":455336,"name":"Gustavo Brum","orcid":"0000-0002-6459-5934","position":4,"is_corresponding":false},{"id":455332,"name":"Juan J. Ferreira","orcid":"0000-0001-8175-9067","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T22:02:48.683291Z","pmid":"32991741","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":[]}