| First Author | Majer M | Year | 2021 |
| Journal | Int J Mol Sci | Volume | 22 |
| Issue | 11 | PubMed ID | 34064290 |
| Mgi Jnum | J:322202 | Mgi Id | MGI:6753426 |
| Doi | 10.3390/ijms22115458 | Citation | Majer M, et al. (2021) Loss of PKGIbeta/IRAG1 Signaling Causes Anemia-Associated Splenomegaly. Int J Mol Sci 22(11) |
| abstractText | 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 Ibeta (PKGIbeta) and the inositol triphosphate receptor I (IP3R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIbeta, regulating cGMP-mediated IP3-dependent Ca(2+)-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 PKGIbeta 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-particularly a strong decrease in the PKGIbeta-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 PKGIbeta/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 PKGIbeta protein functions. |
