Signal Transduction and Function of cGMP/cGMP-dependent Protein Kinase Isozymes.

• Applicant: Professor Dr. Franz Hofmann
• Subject Area: Pharmacology
• Term: from 2007 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 40833648

The second messenger cGMP mediates many useful, but also unwanted effects of the endogenous signaling molecules such as nitric oxide (NO), carbon monoxide (CO) and natriuretic peptides (NP, i.e. ANP, BNP, CNP). A better understanding of the signal transduction pathways initiated by cGMP could generate new therapeutic targets. Research in this area has concentrated on the patho-physiological role of cGMP-dependent protein kinases (cGK) and phosphodiesterases. cGKs are encoded by two genes, cgkl and cgkll. Effects of cGMP in the cardiovascular system are mainly mediated by cGKI. Alternative splicing of the amino-terminus generates two isozymes, the cGKIa and cGKIß that are expressed in a wide variety of cells including neurons, blood and smooth muscle cells. Deletion of exon 10 in the cgkl gene in mice resulted in a multiple morbid animal including changes in blood pressure, vascular remodeling, axonal path finding, learning and memory, recruiting granulocytes to inflammatory sites, plasticity of smooth muscle cells and neuronal synapses. These animals are difficult to analyze, because they die during the first 6 weeks. So far, we were unable to investigate the cardiovascular significance of the two isozymes cGKIa and cGKIß. We have now established two mouse lines that express the la or the Iß isozyme specifically in all smooth muscle cells. Remarkably, both mouse lines live up to a year without showing an overt phenotype. These mouse lines will allow analyzing the cardiovascular function of the cGKI isozymes in adult "healthy" animals.

• DFG Programme: Research Grants