Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

Abstract

Inositol 1,4,5triphosphate receptorassociated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMPdependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP3RI). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMPmediated IP3dependent 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 PKGIβ to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1KO mice developed gastrointestinal bleeding, anemiaassociated splenomegaly and iron deficiency. Additionally, Irag1deficiency 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 mRNAexpression 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 Irag1deficient mice are possible in vivo model to investigate PKGIβ protein functions.

Rare case of upper gastrointestinal hemorrhage due to accessory spleen: A case report

“…This was likely the cause of severe anemia in the patient 3 years prior to the study, or anemia was the cause of splenomegaly. [ 15 ] It was also considered that the abnormally proliferating accessory spleen compressed the branches of the splenic vein, which could have caused the dilation and rupture of veins in the gastric fundus. After the accessory spleen enlarged further, its demand for blood supply increased, and, at the same time, the blood vessels entering and leaving the accessory spleen became enlarged.…”

Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2

“…This translocation could not be observed in vascular smooth muscle cells (VSMCs) of global Irag1 -deficient mice [ 4 ]. However, the loss of the interaction between IRAG1 and PKGIβ may be the reason why protein expression of PKGIβ is reduced in Irag1 mouse mutants [ 3 , 4 , 16 , 17 ]. In contrast, the coiled-coil domain of IRAG1 is not involved in any interaction between IRAG1 and PKGIβ, but is necessary for the interaction of IRAG1 with the IP 3 R-I [ 1 ].…”

“…These pathological changes could also be observed in global Irag1 -/- mice [ 4 ]. Further studies with these transgenic mice revealed that they had iron deficiency anemia as a result of gastrointestinal bleeding and subsequently developed splenomegaly [ 16 ]. The results verified indications of splenomegaly in earlier studies of Irag1 mouse mutants [ 3 , 4 ].…”

“…The results verified indications of splenomegaly in earlier studies of Irag1 mouse mutants [ 3 , 4 ]. Interestingly, these findings occurred mainly in female Irag1 -deficient mice [ 16 ]. In this context, it was shown that IRAG1 has a function in the development of achalasia.…”

Editorial of the Special Issue: cGMP-Signaling in Cells and Tissues: Molecular, Functional and Pharmacological Aspects

“…This is accompanied by downregulation of the specific β-isoform of PKGI (PKGIβ) protein. This leads to the hypothesis, that a loss of PKGIβ/IRAG1 signaling causes these physiological defects [ 8 ].…”