Funktionelle Charakterisierung des cGMP-abhängigen Proteinkinase-Substrates IRAG und des potentiellen "second messenger" zyklisches Cytidin-3',5'-monophosphat im glatten Muskel

Matthias Desch
2010
The NO/cGMP- and ANP/cGMP - cGKI signaling pathway plays an important role for various physiological and pathophysiological processes like relaxation and proliferation of smooth muscle tissue, neurotransmission or activation or inhibition of platelet function. cGKI preferentially modulates intracellular potassium concentration and thereby influences contractility of smooth muscle tissue. The IP3-Receptor associated cGKI substrate IRAG forms a trimeric complex with the IP3RI and cGKIbeta at the
more » ... nd cGKIbeta at the endoplasmatic reticulum. In previous publications a defect in potassium regulation in cardiovascular and gut tissue was shown using IRAG-mutant mice (IRAG D12, interaction site of IRAG with IP3RI is disrupted). To characterize detailed physiological functions of IRAG via the NO/cGMP and ANP/cGMP pathways the IRAG-KO-mousestrain was analyzed in this work. Gut and cardiovascular tissue exhibited a defect in cGMP-mediated relaxation of hormone-induced tonus. This reduced relaxation was detectable with all used cGKI activating compounds (direct cGKI stimulation with cGMP analogues, endogenous stimulation of NO synthesis, exogenous DEA-NO application or exogenous application of ANP). Therefore IRAG plays a crucial role for hormone-induced tonus regulation via the cGKI signaling system. Radiotelemetric blood pressure measurements of IRAG-deficient animals resulted in non significant differences in mean arterial blood pressure (MAP), heart rate, pulse pressure and activity of the animals during light and dark periods. MAP reduction after i.p. application of DETA-NO, SNP and YC-1 was not altered in IRAG-KO animals in comparison to wild type mice. IRAG seems teo be disposable for sustaining basal blood pressure under physiological conditions. However, under pathophysiological conditions like severe sepsis (induced by LPS-application) the drop of MAP was significantly reduced in IRAG-KO-mice in comparison to wildtype-animals. IRAG seems to influence MAP under pathophysiological conditions like systemic inflammation with excessive NO [...]
doi:10.5283/epub.15466 fatcat:crg2vqxyjfh5fokbsbqofdkthi