{"doi":"10.1093/function/zqae007","title":"The Reappraisal of the Reappraisal—CRAC Channels Are Activated by L-Type Ca2+ Channel Blockers, Reply to Bird et al","abstract":"A Perspective on 'A Reappraisal of the Effects of L-type Ca(2+) Channel Blockers on Store-Operated Ca(2+) Entry and Heart Failure' Over a decade ago, we showed that differentiated, contractile arterial myocytes do not express functional Ca 2+ release-activated Ca 2+ (CRAC) channels that mediate store-operated Ca 2+ entry (SOCE).However, CRAC currents emerge in dedifferentiated fibroproliferative non-contractile arterial myocytes because of increased expression of STIM1 and Orai1 1,2 .Dedifferentiated myocytes (called synthetic) are a hallmark of neointimal hyperplasia in diseases such as hypertension, restenosis and atherosclerosis.The emergence of CRAC channels is only one aspect of synthetic myocytes.Synthetic myocytes remodel their ion channel repertoire to promote hyperplasia and migration at the expense of excitability and contractility.Synthetic myocytes downregulate the major orchestrators of excitation-contraction coupling: dihydropyridinesensitive voltage-gated L-type Ca 2+ channels (Ca v 1.2) and ryanodine receptors (for review 3 ).Recently, we examined the effects of Ca V 1.2 channel antagonists on synthetic arterial myocytes (Johnson et al 4 ).We reported that Ca V 1.2 channels blockers at concentrations ranging from 0.5-20 µM increased intracellular Ca 2+ in synthetic arterial myocytes.Our data support the idea that Ca V 1.2 channel blockers, including amlodipine, nifedipine, verapamil, and diltiazem activate STIM proteins and CRAC channels independently of store depletion 4 .We further showed that 0.5 µM amlodipine synergizes with sub-optimal concentrations of the platelet-derived growth factor (0.5 ng/mL PDGF) in a STIM1-dependent manner to induce arterial myocyte proliferation and migration to levels approaching those produced by maximal PDGF stimulation (10 ng/mL).Bird et al 5 challenged our study and contended that our findings represent an artifact of fluorescence Ca 2+ measurements because \"amlodipine is strongly fluorescent in the cytoplasm with an excitation spectrum that overlaps with that of fura-2\".They reported Ca 2+ imaging experiments using the single-excitation/single-emission dye Cal520 but did not attempt to replicate our key biological observations, most notably the synergistic effects of 0.5 M amlodipine on PDGF-triggered arterial myocyte proliferation and migration, and their dependence on STIM1 (Figure 1H-K; Figure 7A-G; Figure","journal":"Function","year":2024,"id":460749,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":655752,"name":"Khaled Machaca","orcid":"0000-0001-6215-2411","position":1,"is_corresponding":false},{"id":618122,"name":"Patrick G. Hogan","orcid":"0000-0001-9869-0684","position":2,"is_corresponding":false},{"id":262132,"name":"Mohamed Trebak","orcid":"0000-0001-6759-864X","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T02:04:07.925246Z","pmid":"38486979","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":[]}