{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T14:17:28Z","timestamp":1764857848593,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO\/cGMP-signaling pathway and forms a ternary complex with the cGMP-dependent protein kinase I\u03b2 (PKGI\u03b2) and the inositol triphosphate receptor I (IP3R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGI\u03b2, regulating cGMP-mediated IP3-dependent Ca2+-release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO\/cGMP\/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGI\u03b2 to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1-KO mice developed gastrointestinal bleeding, anemia-associated splenomegaly and iron deficiency. Additionally, Irag1-deficiency altered the protein levels of some cGMP\/PKGI signaling proteins\u2014particularly a strong decrease in the PKGI\u03b2\u2014in the colon, spleen and stomach but did not change mRNA-expression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGI\u03b2\/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1-deficient mice are possible in vivo model to investigate PKGI\u03b2 protein functions.<\/jats:p>","DOI":"10.3390\/ijms22115458","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T13:15:15Z","timestamp":1621602915000},"page":"5458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Loss of PKGI\u03b2\/IRAG1 Signaling Causes Anemia-Associated Splenomegaly"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2142-8420","authenticated-orcid":false,"given":"Michael","family":"Majer","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally","family":"Prueschenk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-6839","authenticated-orcid":false,"given":"Jens","family":"Schlossmann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/35004606","article-title":"Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase I\u03b2","volume":"404","author":"Schlossmann","year":"2000","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"24153","DOI":"10.1074\/jbc.M101530200","article-title":"Molecular determinants of the interaction between the inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) and cGMP kinase I\u03b2","volume":"276","author":"Ammendola","year":"2001","journal-title":"J. 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