Professor

Jens Schlossmann

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Phone: +49 941 943-4770

Fax:? ? ?+49 941 943-4772

E-Mail:?jens.schlossmann@ur.de

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Field of Research:

• The regulation of intracellular calcium release is essential for various cellular processes, including proliferation and contractility of smooth muscle tone. NO/cGMP kinase I (cGKI) signalling is a major mechanism leading to reduction of calcium release which induces smooth muscle relaxation.

  Our studies are focused to elucidate the signal transduction pathways and substrates of the cGMP-dependent protein kinase (cGK) and its regulatory roles for calcium signalling. Thereby, we identified the 125-135 kDa microsomal membrane protein IRAG (IP₃R associated cGMP kinase substrate). IRAG is found in a macrocomplex in association with cGKIβ and the InsP₃ receptor type I (IP₃RI) in various tissues including aorta, intestine, trachea and platelets. The specificity of the interaction IRAG with cGKIβ and IP₃RI was shown by the yeast two-hybrid system and by co-precipitation of expressed proteins. Targeted deletion of exon 12 of murine IRAG which codes for the N-terminal part of the coiled-coil domain disrupted the IRAG-IP₃RI interaction in vivo and resulted in hypomorphic IRAG^Δ12/Δ12 mice. These mice have a strong gastrointestinal dilation and a severely reduced gastrointestinal motility. The relaxation of hormone-contracted IRAG^Δ12/Δ12smooth muscle by cGMP was abolished. Furthermore, Norepinephrine-induced increases of [Ca²⁺]_i in aortic smooth muscle cells from IRAG^Δ12/Δ12mice were not decreased by cGMP. This suggests, that interaction of cGKI-IRAG with IP₃RI is essential for cGMP-dependent relaxation of hormone-contracted smooth muscle. Interestingly, blood pressure of IRAG^Δ12/Δ12mice measured by telemetry was only marginally reduced by nitric oxide donors.

  Furthermore, NO/cGMP signaling in platelets is strongly dependent on the IRAG/IP₃RI interaction suggesting that IRAG is strongly involved in the inhibition of NO/cGMP-mediated platelet aggregation and thrombus formation.

  Recent research is focused on the role of cGMP/cGK in the kidney. Thereby, it was elucidated that cGKIα suppressed kidney fibrosis via the RhoA/ROCK signalling pathway.