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Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that facilitates numerous signal transduction pathways; its production in cells is tightly balanced by ligand\u2010stimulated receptors that activate adenylate cyclases (ACs), that is, \u201csource\u201d and by phosphodiesterases (PDEs) that hydrolyze it, that is, \u201csinks.\u201d Because it regulates various cellular functions, including cell growth and differentiation, gene transcription and protein expression, the cAMP signaling pathway has been exploited for the treatment of numerous human diseases. Reduction in cAMP is achieved by blocking \u201csources\u201d; however, elevation in cAMP is achieved by either stimulating \u201csource\u201d or blocking \u201csinks.\u201d Here we discuss an alternative paradigm for the regulation of cellular cAMP via GIV\/Girdin, the prototypical member of a family of modulators of trimeric GTPases, Guanine nucleotide Exchange Modulators (GEMs). Cells upregulate or downregulate cellular levels of GIV\u2010GEM, which modulates cellular cAMP via spatiotemporal mechanisms distinct from the two most often targeted classes of cAMP modulators, \u201csources\u201d and \u201csinks.\u201d A network\u2010based compartmental model for the paradigm of GEM\u2010facilitated cAMP signaling has recently revealed that GEMs such as GIV serve much like a \u201ctunable valve\u201d that cells may employ to finetune cellular levels of cAMP. Because dysregulated signaling via GIV and other GEMs has been implicated in multiple disease states, GEMs constitute a hitherto untapped class of targets that could be exploited for modulating aberrant cAMP signaling in disease states.<\/jats:p><jats:p>This article is categorized under:<jats:list list-type=\"simple\">\n<jats:list-item><jats:p>Models of Systems Properties and Processes &gt; Mechanistic Models<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Biological Mechanisms &gt; Cell Signaling<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wsbm.1490","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T11:50:50Z","timestamp":1587642650000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Regulating cellular cyclic adenosine monophosphate: \u201cSources,\u201d \u201csinks,\u201d and now, \u201ctunable valves\u201d"],"prefix":"10.1002","volume":"12","author":[{"given":"Michael","family":"Getz","sequence":"first","affiliation":[{"name":"Chemical Engineering Graduate Program University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5953-4347","authenticated-orcid":false,"given":"Padmini","family":"Rangamani","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8917-3201","authenticated-orcid":false,"given":"Pradipta","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California USA"},{"name":"Department of Cellular and Molecular Medicine University of California San Diego  La Jolla California USA"},{"name":"Moores Comprehensive Cancer Center University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"e_1_2_9_1_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-7-24"},{"key":"e_1_2_9_1_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2391"},{"key":"e_1_2_9_1_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2014.01.040"},{"key":"e_1_2_9_1_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.06.005"},{"key":"e_1_2_9_2_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910320622"},{"key":"e_1_2_9_2_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep19577"},{"key":"e_1_2_9_2_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22001"},{"key":"e_1_2_9_2_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100195"},{"key":"e_1_2_9_2_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500586200"},{"key":"e_1_2_9_2_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201500133"},{"key":"e_1_2_9_2_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.07091"},{"key":"e_1_2_9_2_9_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.21837"},{"key":"e_1_2_9_2_10_1","doi-asserted-by":"publisher","DOI":"10.3109\/02713688209019996"},{"key":"e_1_2_9_2_11_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e12-02-0133"},{"key":"e_1_2_9_2_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm911"},{"key":"e_1_2_9_2_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"e_1_2_9_2_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407009101"},{"key":"e_1_2_9_2_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5147"},{"key":"e_1_2_9_2_16_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.6.1897"},{"key":"e_1_2_9_2_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(83)92084-6"},{"key":"e_1_2_9_2_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5851-09.2010"},{"key":"e_1_2_9_2_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.06.026"},{"issue":"22","key":"e_1_2_9_2_20_1","first-page":"7093","article-title":"Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: New approaches to therapy","volume":"50","author":"Cho\u2010Chung Y. 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