{"doi":"10.1111/jne.12974","title":"Cyclic AMP‐dependent activation of ERK via GLP‐1 receptor signalling requires the neuroendocrine cell‐specific guanine nucleotide exchanger NCS‐RapGEF2","abstract":"Abstract Cyclic AMP activation of the Rap‐Braf‐MEK‐ERK pathway after signalling initiated by the neuropeptide pituitary adenylate cyclase‐activating peptide (PACAP), via the G s ‐protein coupled receptor (G s PCR) PAC1, occurs uniquely through the neuritogenic cAMP sensor Rap guanine nucleotide exchange factor 2 (NCS‐RapGEF2) in Neuroscreen‐1 (NS‐1) neuroendocrine cells. We examined the expression of other Family B G s PCRs in this cell line and assessed cAMP elevation and neuritogenesis after treatment with their cognate peptide ligands. Exposure of NS‐1 cells to the VIPR1/2 agonist vasoactive intestinal polypeptide, or the GLP1R agonist exendin‐4, did not induce neuritogenesis, or elevation of cAMP, presumably as a result of insufficient receptor protein expression. Vasoactive intestinal polypeptide and exendin‐4 did induce neuritogenesis after transduction of human VIPR1, VIPR2 and GLP1R into NS‐1 cells. Exendin‐4/GLP1R‐stimulated neuritogenesis was MEK‐ERK‐dependent (blocked by U0126), indicating its use of the cAMP→RapGEF2→ERK neuritogenic signalling pathway previously identified for PACAP/PAC1 signalling in NS‐1 cells. NCS‐RapGEF2 is expressed in the rodent insulinoma cell lines MIN6 and INS‐1, as well as in human pancreatic islets. As in NS‐1 cells, exendin‐4 caused ERK phosphorylation in INS‐1 cells. Reduction in RapGEF2 expression after RapGEF2‐shRNA treatment reduced exendin‐4‐induced ERK phosphorylation. Transcriptome analysis of INS‐1 cells after 1 hour of exposure to exendin‐4 revealed an immediate early‐gene response that was composed of both ERK‐dependent and ERK‐independent signalling targets. We propose that cAMP signalling initiated by glucagon‐like peptide 1 (GLP‐1) in pancreatic beta cells causes parallel activation of multiple cAMP effectors, including NCS‐RapGEF2, Epac and protein kinase A, to separately control various facets of GLP‐1 action, including insulin secretion and transcriptional modulation.","journal":"Journal of Neuroendocrinology","year":2021,"id":201165,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"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":502205,"name":"Sam P. Dahlke","orcid":null,"position":1,"is_corresponding":false},{"id":779501,"name":"Andrew C. Emery","orcid":"0000-0002-6760-2570","position":2,"is_corresponding":false},{"id":779920,"name":"Michelle Sung","orcid":null,"position":3,"is_corresponding":false},{"id":429774,"name":"Oleg G. Chepurny","orcid":"0009-0002-2003-0752","position":4,"is_corresponding":false},{"id":429775,"name":"George G. Holz","orcid":"0000-0002-1781-3580","position":5,"is_corresponding":false},{"id":364740,"name":"Lee E. Eiden","orcid":"0000-0001-7524-944X","position":6,"is_corresponding":false},{"id":501400,"name":"Wenqin Xu","orcid":"0000-0001-8813-8183","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:50:52.535403Z","pmid":"33960038","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":[]}