{"doi":"10.17615/21e2-k543","title":"A chemical-genetic approach to study G protein regulation of   cell function in vivo","abstract":"Impaired functioning of pancreatic β cells is a key hallmark of type 2 diabetes. β cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific β cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that β cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific β cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in β cells only. Importantly, the two designer receptors differed in their G protein-coupling properties (Gq/11 versus Gs). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either β cell Gq/11 or Gs G proteins. Here we report the findings that conditional and selective activation of β cell Gq/11 signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated β cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of β cell Gs triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of β cell function in vivo.","journal":"UNC Libraries","year":2020,"id":114580,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"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":539054,"name":"E. Rosemond","orcid":null,"position":1,"is_corresponding":false},{"id":535382,"name":"H. Lu","orcid":"0000-0002-1924-8626","position":2,"is_corresponding":false},{"id":201959,"name":"X. Ma","orcid":null,"position":3,"is_corresponding":false},{"id":169809,"name":"J. H. Li","orcid":null,"position":4,"is_corresponding":false},{"id":539055,"name":"M. Scarselli","orcid":null,"position":5,"is_corresponding":false},{"id":539056,"name":"J.-M. Guettier","orcid":null,"position":6,"is_corresponding":false},{"id":539057,"name":"F. J. Gonzalez","orcid":null,"position":7,"is_corresponding":false},{"id":539058,"name":"D. Gautam","orcid":null,"position":8,"is_corresponding":false},{"id":539059,"name":"I. R. de Azua","orcid":null,"position":9,"is_corresponding":false},{"id":539060,"name":"Barbara Armbruster","orcid":null,"position":10,"is_corresponding":false},{"id":534381,"name":"J. Wess","orcid":null,"position":11,"is_corresponding":false},{"id":396199,"name":"B. L. Roth","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:29.674622Z","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":[]}