{"doi":"10.1101/2021.09.03.458925","title":"Glucagon Receptor-mediated Regulation of Gluconeogenic Gene Transcription is Endocytosis-dependent in Primary Hepatocytes","abstract":"Abstract A number of G protein-coupled receptors (GPCRs) are now thought to use endocytosis to promote cellular cAMP signaling that drives downstream transcription of cAMP-dependent genes. We tested if this is true for the Glucagon Receptor (GCGR), which mediates physiological regulation of hepatic glucose metabolism via cAMP signaling. We show that epitope-tagged GCGRs undergo clathrin and dynamin-dependent endocytosis in HEK293 cells after activation by glucagon, and transit via EEA1-marked endosomes shown previously to be sites of GPCR/Gs-stimulated production of cAMP. We further show that endocytosis potentiates cytoplasmic cAMP elevation produced by GCGR activation and promotes transcription of PCK1 , the gene which encodes the enzyme catalyzing the rate-limiting step in gluconeogenesis. We verify endocytosis-dependent induction of PCK1 expression by endogenous GCGRs in primary hepatocytes, and show similar control of two other gluconeogenic genes ( PGC1α and G6PC ). Together, these results implicate the endosomal signaling paradigm in metabolic regulation by glucagon.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226486,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"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":829871,"name":"Mark E. von Zastrow","orcid":null,"position":1,"is_corresponding":false},{"id":638295,"name":"Erica L. Sanchez","orcid":"0000-0002-9079-1090","position":2,"is_corresponding":false},{"id":829527,"name":"Jan Mikhale B. Cajulao","orcid":"0000-0002-8003-5144","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":null,"created_at":"2026-07-18T23:54:34.185847Z","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":[]}