{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:02:04Z","timestamp":1792206124132,"version":"4.4.0"},"reference-count":150,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL111582"],"award-info":[{"award-number":["HL111582"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL111582"],"award-info":[{"award-number":["HL111582"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ca2+ is a universal intracellular signal. The modulation of cytoplasmic Ca2+ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation\u2013contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers\u2014cyclic adenosine monophosphate (cAMP), Ca2+, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca2+ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca2+ signaling when activated by mechanisms involving Ca2+ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca2+ levels. It does so by regulating the activity of Ca2+ signaling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca2+ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer\u2019s disease, hypertension, and atherosclerosis, among other diseases.<\/jats:p>","DOI":"10.3390\/ijms21051616","type":"journal-article","created":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T09:30:36Z","timestamp":1582882236000},"page":"1616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Integration of Rap1 and Calcium Signaling"],"prefix":"10.3390","volume":"21","author":[{"given":"Ramoji","family":"Kosuru","sequence":"first","affiliation":[{"name":"Versiti Blood Research Institute, Milwaukee, WI 53201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Chrzanowska","sequence":"additional","affiliation":[{"name":"Versiti Blood Research Institute, Milwaukee, WI 53201, USA"},{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, PO Box 2178, Milwaukee, WI 53201-2178, USA"},{"name":"Cardiovascular Center, Medical College of Wisconsin, PO Box 2178, Milwaukee, WI 53201-2178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1073\/pnas.86.1.162","article-title":"Detection of genes with a potential for suppressing the transformed phenotype associated with activated ras genes","volume":"86","author":"Noda","year":"1989","journal-title":"Proc. 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