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)的许多有用的、但也是不必要的作用。更好地了解cGMP启动的信号转导通路可能会产生新的治疗靶点。这方面的研究主要集中在cGMP依赖的蛋白激酶(CGK)和磷酸二酯酶的病理生理作用上。CGKs由cgk1和cgk11两个基因编码。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了两种同工酶，cGKIa和cGKI？，它们在包括神经元、血液和平滑肌细胞在内的各种细胞中都有表达。Cgk1基因外显子10的缺失导致了一种多病态动物，包括血压、血管重构、轴突寻路、学习和记忆、粒细胞向炎症部位募集、平滑肌细胞可塑性和神经元突触的变化。这些动物很难分析，因为它们在最初的6周内死亡。到目前为止，我们还不能研究cGKIa和cGKI？这两种同工酶在心血管疾病中的意义。我们现在已经建立了两个小鼠系，它们在所有的平滑肌细胞中特异地表达LA或I？同工酶。值得注意的是，这两个品系的小鼠都活了一年，没有表现出明显的表型。这些小鼠品系将可以分析成年“健康”动物的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.