{"doi":"10.1101/2020.10.29.360784","title":"Purinergic P2Y1 and P2Y2/4 receptors elicit distinct Ca <sup>2+</sup> signaling patterns in hepatocytes via differential feedback regulation by Protein Kinase C","abstract":"Abstract Extracellular nucleotides are key regulators of liver physiology. In primary rat hepatocytes, P2Y1 receptor (P2Y1R) activation by ADP generates cytosolic calcium ([Ca 2+ ] c ) oscillations with narrow spikes, whereas P2Y2/4R activation by UTP led to more complex broad [Ca 2+ ] c oscillations. Both [Ca 2+ ] c oscillation signatures were observed with the common agonist ATP. Inhibition of Gα q signaling with YM-254890 abolished ATP-induced [Ca 2+ ] c oscillations, indicating that they depend on inositol 1,4,5-trisphosphate (IP 3 ), and are not mediated by P2X receptors. The narrow P2Y1-linked [Ca 2+ ] c spikes and the broad P2Y2/4-linked [Ca 2+ ] c spikes are shaped by differential and complex PKC-mediated feedback mechanisms. Downregulation of PKC broadened both ADP- and UTP-induced [Ca 2+ ] c oscillations, with a more pronounced effect on the former. PKC downregulation also selectively elicited a more robust response to ADP stimulation, enhancing oscillatory and sustained [Ca 2+ ] c responses. Acute PKC modulation confirmed the importance of the negative PKC feedback regulation of P2Y1R-linked [Ca 2+ ] c signals; such that PKC activation decreased [Ca 2+ ] c oscillation frequency and PKC inhibition increased [Ca 2+ ] c spike width. However, both PKC activation and inhibition decreased the spike width of P2Y2/4R-induced [Ca 2+ ] c oscillations, suggesting that multiple opposing PKC feedback mechanisms shape P2Y2/4R responses. Significantly, plasma membrane Ca 2+ entry was required for negative PKC feedback on P2Y1R-linked [Ca 2+ ] c oscillations, whereas P2Y2/4R-linked [Ca 2+ ] c oscillations were less sensitive to negative regulation by PKC and independent of Ca 2+ influx. Thus, differential feedback regulation by PKC gives rise to receptor-specific [Ca 2+ ] c oscillation profiles, which can encode the diverse physiological and pathophysiological responses to distinct agonists that all act through the IP 3 signaling cascade.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127603,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"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":396747,"name":"Paula J. Bartlett","orcid":"0000-0002-4089-1288","position":1,"is_corresponding":false},{"id":577891,"name":"Robert Brumer","orcid":null,"position":2,"is_corresponding":false},{"id":576957,"name":"Lawrence D. Gaspers","orcid":"0000-0002-5620-3283","position":3,"is_corresponding":false},{"id":259871,"name":"Henning Ulrich","orcid":"0000-0002-2114-3815","position":4,"is_corresponding":false},{"id":396749,"name":"Andrew P. Thomas","orcid":"0000-0002-9026-7467","position":5,"is_corresponding":false},{"id":576956,"name":"Juliana Corrêa-Velloso","orcid":"0000-0002-1276-3844","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-18T23:15:34.966380Z","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":[]}