{"doi":"10.1016/j.jbc.2021.101118","title":"Shining light on location-biased cAMP signaling","abstract":"cAMP is the indispensable second messenger regulating cell metabolism and function in response to extracellular hormones and neurotransmitters. cAMP is produced via the activation of G protein–coupled receptors located at both the cell surface and inside the cell. Recently, Tsvetanova et al. explored cAMP generation in distinct locations and the impact on respective cell functions. Using a phospho-proteomic analysis, they provide insight into the unique role of localized cAMP production in cellular phospho-responses. cAMP is the indispensable second messenger regulating cell metabolism and function in response to extracellular hormones and neurotransmitters. cAMP is produced via the activation of G protein–coupled receptors located at both the cell surface and inside the cell. Recently, Tsvetanova et al. explored cAMP generation in distinct locations and the impact on respective cell functions. Using a phospho-proteomic analysis, they provide insight into the unique role of localized cAMP production in cellular phospho-responses. Similar to other extracellular stimuli, hormones and neurotransmitters transmit signals into cells by binding to different G protein–coupled receptors (GPCRs), which constitute the largest receptor family in the body. Peptidic and nonpeptidic hormones such as vasopressin and epinephrine, respectively, activate distinct GPCRs to induce the synthesis of cAMP, the second messenger molecule that activates PKA, which in turn regulates numerous metabolic functions (e.g., glycogen metabolism, water homeostasis). The established paradigm of GPCR signaling via cAMP postulates that ligand binding to its cognate receptor induces conformational changes to the latter, enabling coupling and activation of the heterotrimeric Gs protein, the guanine nucleotide-binding protein that stimulates activity of transmembrane adenylate cyclase (AC) localized at the plasma membrane. Activated AC converts ATP into cAMP, a reaction that is rapidly terminated by the GTPase activity of Gs and by a cascade of reactions and interactions that desensitize the ligand-activated receptor, including (1) receptor phosphorylation, (2) interaction of the phosphorylated receptor with β-arrestins, and (3) internalization of the receptor–arrestin complex into early endosomes. Once in endosomes, the agonist dissociates from the receptor and the receptor is either degraded in lysosomes (downregulation) or dephosphorylated and recycled back to the plasma membrane for a new cycle of activation and signaling (resensitization) (reviewed in (1Sutkeviciute I. Vilardaga J.P. Structural insights into emergent signaling modes of G protein-coupled receptors.J. Biol. Chem. 2020; 295: 11626-11642Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar)). Following initial studies on the parathyroid hormone and thyroid-stimulating hormone receptors back in 2009, another mode of cAMP signaling has been identified for several other GPCRs (reviewed in (1Sutkeviciute I. Vilardaga J.P. Structural insights into emergent signaling modes of G protein-coupled receptors.J. Biol. Chem. 2020; 295: 11626-11642Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar)). In this recently recognized model, receptors continue to signal through Gs after internalization into early endosomes to induce a second wave of cAMP production that not only causes unique pharmacological responses (2Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. Gardella T.J. Vilardaga J.P. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5: 734-742Crossref PubMed Scopus (367) Google Scholar, 3Vilardaga J.P. Jean-Alphonse F.G. Gardella T.J. Endosomal generation of cAMP in GPCR signaling.Nat. Chem. Biol. 2014; 10: 700-706Crossref PubMed Scopus (130) Google Scholar) but also likely has physiological relevance for human health and disease (4White A.D. Fang F. Jean-Alphonse F.G. Clark L.J. An H.J. Liu H. Zhao Y. Reynolds S.","journal":"Journal of Biological Chemistry","year":2021,"id":208474,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9414,"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":281859,"name":"Ieva Sutkevičiu̅tė","orcid":"0000-0002-2168-3344","position":1,"is_corresponding":false},{"id":644073,"name":"Karina A. Peña","orcid":"0000-0001-6401-5269","position":2,"is_corresponding":false},{"id":281860,"name":"Jean‐Pierre Vilardaga","orcid":"0000-0002-1217-1435","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:51:57.582057Z","pmid":"34437901","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":[]}