Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly
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 Iβ (PKGIβ) and the inositol triphosphate receptor I (IP<sub>3</sub>R-I). Functional s...
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5458 |
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| author | Michael Majer Sally Prueschenk Jens Schlossmann |
| author_facet | Michael Majer Sally Prueschenk Jens Schlossmann |
| author_sort | Michael Majer |
| collection | DOAJ |
| description | 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 Iβ (PKGIβ) and the inositol triphosphate receptor I (IP<sub>3</sub>R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMP-mediated IP<sub>3</sub>-dependent Ca<sup>2+</sup>-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 PKGIβ 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, <i>Irag1</i>-deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in 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 PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global <i>Irag1</i>-deficient mice are possible in vivo model to investigate PKGIβ protein functions. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:09:10Z |
| publishDate | 2021-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3e6ba87efc9f460db88ad3d8ed3f17b42023-11-21T20:52:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211545810.3390/ijms22115458Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated SplenomegalyMichael Majer0Sally Prueschenk1Jens Schlossmann2Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, GermanyDepartment of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, GermanyDepartment of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, GermanyInositol 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 Iβ (PKGIβ) and the inositol triphosphate receptor I (IP<sub>3</sub>R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMP-mediated IP<sub>3</sub>-dependent Ca<sup>2+</sup>-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 PKGIβ 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, <i>Irag1</i>-deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in 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 PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global <i>Irag1</i>-deficient mice are possible in vivo model to investigate PKGIβ protein functions.https://www.mdpi.com/1422-0067/22/11/5458anemiaIP<sub>3</sub>R-Iiron deficiencyIRAGIRAG1MRVI1 |
| spellingShingle | Michael Majer Sally Prueschenk Jens Schlossmann Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly International Journal of Molecular Sciences anemia IP<sub>3</sub>R-I iron deficiency IRAG IRAG1 MRVI1 |
| title | Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly |
| title_full | Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly |
| title_fullStr | Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly |
| title_full_unstemmed | Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly |
| title_short | Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly |
| title_sort | loss of pkgiβ irag1 signaling causes anemia associated splenomegaly |
| topic | anemia IP<sub>3</sub>R-I iron deficiency IRAG IRAG1 MRVI1 |
| url | https://www.mdpi.com/1422-0067/22/11/5458 |
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