{"doi":"10.1007/s11302-025-10070-1","title":"A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C","abstract":"Abstract Activation of PLCβ enzymes by G iβγ and G αq/11 proteins is a common mechanism to trigger cytosolic Ca 2+ increase. We and others reported that G αq/11 inhibitor FR900359 (FR) can inhibit both G αq - and, surprisingly, G iβγ -mediated intracellular Ca 2+ mobilization. Thus, the G αi -G βγ -PLCβ-Ca 2+ signaling axis depends entirely on the presence of active G αq , which reasonably explained FR-inhibited G iβγ -induced Ca 2+ release. However, the conclusion that G iβγ signaling is controlled by G αq derives mostly from HEK293 cells. Here we show that indeed in HEK293 cells both G αq/11 siRNA and G αq/11 inhibitors diminished Ca 2+ increase triggered by native G q -coupled P2Y 1 receptors, or by transfected G i -coupled A 1 - or G s -coupled A 2B adenosine receptors (ARs). However, in T24 bladder cancer cells, G i inhibitor PTX, but not G αq/11 inhibitors, FR, YM254890 (YM) or G q/11 siRNA, inhibited Ca 2+ increase triggered by native A 2B AR activation. Simultaneous inactivation of G i and G s further suppressed A 2B AR-triggered Ca 2+ increase in T24 cells. The G αq/11 inhibitor YM fully and partially inhibited endogenous P2Y 1 - and β 2 -adrenergic receptor-induced Ca 2+ increase in T24 cells, respectively. PKC activator PMA partially diminished A 2B AR-triggered but completely diminished β 2 -adrenergic receptor-triggered Ca 2+ increase in T24 cells. Neither β-arrestin1 nor β-arrestin2 siRNA affected A 2B AR-mediated Ca 2+ increase. Unlike in T24 cells, YM inhibited native A 2B AR-triggered calcium mobilization in MDA-MB-231 breast cancer cells. Thus, G αq/11 is vital for Ca 2+ increase in some cell types, but G iβγ -mediated Ca 2+ signaling can be Gα q/11 -dependent or independent based on cell type and receptor activated. Besides G proteins, PKC also modulates cytosolic Ca 2+ increase depending on cell type and receptor.","journal":"Purinergic Signalling","year":2025,"id":514169,"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":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1286453,"name":"Ray R. Gao","orcid":null,"position":1,"is_corresponding":false},{"id":1359301,"name":"Clayton K. Meyer","orcid":null,"position":2,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":3,"is_corresponding":false},{"id":504396,"name":"Zhan-Guo Gao","orcid":"0009-0006-4777-8647","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"39934472","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":[]}