Cyclic GMP-dependent protein kinases: understanding in vivo functions by gene targeting

Identifying the specific functions that are mediated by cyclic GMP (cGMP)-dependent protein kinases is key to our understanding of the biological role of the nitric oxide/cGMP signaling cascade. Over the last two decades, there have been numerous reports on the functional roles of cGMP kinases. However, most studies have been performed with isolated cells and organs by using specific activators and inhibitors of cGMP kinases. Under such experimental conditions, a clear dissection between the cGMP kinase pathway and other pathways, for example, that of cyclic AMP kinase, has been difficult to achieve. In order to identify biological processes in which cGMP kinases are unambiguously involved, the genes of cGMP kinase I and cGMP kinase II have been deleted in mice. This review focuses on the physiological functions that are regulated by cGMP kinases as revealed by cGMP kinase-deficient animals. For cGMP kinase I, these functions include the contractility of vascular and gastrointestinal smooth muscle and the homeostasis of platelet activity. According to its expression pattern, the Type II cGMP kinase plays a definite biological part in transepithelial Cl- and Na+ transport in the intestine, longitudinal growth of long bones, and the regulation of the kidney renin-angiotensin-aldosterone system. Further, cGMP kinase I and II mutants reveal new aspects for the role of nitric oxide/cGMP in the induction of neuronal plasticity, such as hippocampal long-term potentiation and cerebellar long-term depression. In conclusion, inactivation of the cGMP kinase genes shows that cGMP kinases regulate very specifically distinct cellular functions by pathways that are separate from those used by cyclic AMP kinases. Mice deficient in cGMP kinases exhibit severe defects and, therefore, may serve as animal models for several human diseases, including hypertension, thrombosis, gastrointestinal dysmotility, and dwarfism.