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

第二信使cGMP介导内源性信号分子如一氧化氮（NO），一氧化碳（CO）和利钠肽（NP，即ANP， BNP， CNP）的许多有用但也有害的作用。更好地了解cGMP启动的信号转导途径可以产生新的治疗靶点。该领域的研究主要集中在cgmp依赖性蛋白激酶（cGK）和磷酸二酯酶的病理生理作用上。cGKs由两个基因cgkl和cgkll编码。cGMP在心血管系统中的作用主要由cGKI介导。氨基末端的选择性剪接产生两种同工酶，cGKIa和cgkß，它们在包括神经元、血液和平滑肌细胞在内的多种细胞中表达。小鼠cgkl基因外显子10的缺失会导致多种疾病，包括血压、血管重塑、轴突寻径、学习和记忆、向炎症部位募集粒细胞、平滑肌细胞和神经元突触的可塑性的改变。这些动物很难分析，因为它们在头6周内死亡。到目前为止，我们还无法研究这两种同工酶cGKIa和cgkß的心血管意义。我们现在已经建立了两种小鼠系，它们在所有平滑肌细胞中特异性表达la或isβ同工酶。值得注意的是，这两种小鼠系都能活一年而不表现出明显的表型。这些小鼠系将允许在成年“健康”动物中分析cGKI同工酶的心血管功能。

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.