|
|
Prof. Dr. Jens Schlossmann
Professor and provisional Chairman
|
|
|
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 IRAGΔ12/Δ12
mice. These mice have a strong gastrointestinal dilation and a severely
reduced gastrointestinal motility. The relaxation of hormone-contracted
IRAGΔ12/Δ12 smooth muscle by cGMP was abolished. Furthermore, Norepinephrine-induced increases of [Ca2+]i in aortic smooth muscle cells from IRAGΔ12/Δ12 mice 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 IRAGΔ12/Δ12 mice 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.
Future studies:
-
The aim of the
group is to identify the physiology and the molecular mechanism of the
signal transduction mediated by NO/cGMP/cGKinase-signaling proteins.
For this purpose biochemical, molecular biology, genetic deletion,
immunohistological, physiological and biophysical methods are used.
These studies will lead to a further understanding of the function of
NO/cGMP signal transduction in diverse tissues comprising smooth
muscle, platelets and kidney, its regulation in respect to
intracellular calcium and its physiological and pathophysiological
consequences e.g. for cardiovascular diseases and atherosclerosis.
These studies involve biochemical analysis and genetic studies using
conventional and conditional gene-targeted mutant and knockout mice.
|
|
Funding:
until 2007:
- SFB 391 (Mechanismen der schnellen Zellaktivierung)
- Wilhelm-Sander-Stiftung
- GRK 438 (Vaskuläre Biologie in der Medizin)
|
Tel: +49 941 943-4770
Fax: +49 941 943-4773
E-Mail to Jens Schlossmann
|
