{"doi":"10.3389/fmolb.2021.780865","title":"The Identification of a Novel Calcium-Dependent Link Between NAD+ and Glucose Deprivation-Induced Increases in Protein O-GlcNAcylation and ER Stress","abstract":"The modification of proteins by O-linked β- N -acetylglucosamine (O-GlcNAc) is associated with the regulation of numerous cellular processes. Despite the importance of O-GlcNAc in mediating cellular function our understanding of the mechanisms that regulate O-GlcNAc levels is limited. One factor known to regulate protein O-GlcNAc levels is nutrient availability; however, the fact that nutrient deficient states such as ischemia increase O-GlcNAc levels suggests that other factors also contribute to regulating O-GlcNAc levels. We have previously reported that in unstressed cardiomyocytes exogenous NAD + resulted in a time and dose dependent decrease in O-GlcNAc levels. Therefore, we postulated that NAD + and cellular O-GlcNAc levels may be coordinately regulated. Using glucose deprivation as a model system in an immortalized human ventricular cell line, we examined the influence of extracellular NAD + on cellular O-GlcNAc levels and ER stress in the presence and absence of glucose. We found that NAD + completely blocked the increase in O-GlcNAc induced by glucose deprivation and suppressed the activation of ER stress. The NAD + metabolite cyclic ADP-ribose (cADPR) had similar effects on O-GlcNAc and ER stress suggesting a common underlying mechanism. cADPR is a ryanodine receptor (RyR) agonist and like caffeine, which also activates the RyR, both mimicked the effects of NAD + . SERCA inhibition, which also reduces ER/SR Ca 2+ levels had similar effects to both NAD + and cADPR on O-GlcNAc and ER stress responses to glucose deprivation. The observation that NAD + , cADPR, and caffeine all attenuated the increase in O-GlcNAc and ER stress in response to glucose deprivation, suggests a potential common mechanism, linked to ER/SR Ca 2+ levels, underlying their activation. Moreover, we showed that TRPM2, a plasma membrane cation channel was necessary for the cellular responses to glucose deprivation. Collectively, these findings support a novel Ca 2+ -dependent mechanism underlying glucose deprivation induced increase in O-GlcNAc and ER stress.","journal":"Frontiers in Molecular Biosciences","year":2021,"id":184273,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":477472,"name":"Helen E. Collins","orcid":"0000-0002-9302-6044","position":1,"is_corresponding":false},{"id":611168,"name":"Martin E. Young","orcid":"0000-0001-8360-5029","position":2,"is_corresponding":false},{"id":302763,"name":"Jianhua Zhang","orcid":"0000-0002-2128-9574","position":3,"is_corresponding":false},{"id":232325,"name":"Adam R. Wende","orcid":"0000-0002-5536-4675","position":4,"is_corresponding":false},{"id":242291,"name":"Victor Darley‐Usmar","orcid":"0000-0001-8921-7086","position":5,"is_corresponding":false},{"id":232324,"name":"John C. Chatham","orcid":"0000-0001-7180-9948","position":6,"is_corresponding":false},{"id":739417,"name":"Luyun Zou","orcid":null,"position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:48:26.340498Z","pmid":"34950703","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":[]}