The function of NO-sensitive guanylyl cyclase: What we can learn from genetic mouse models

The signaling molecule nitric oxide (NO) acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal and nervous systems. Two isoforms of NO-GC are known to exist on the protein level. The enzyme is a heterodimer consisting of an alpha (α₁ or α₂) and a beta subunit (β₁). Strategies for the genomic deletion of either subunit have been developed in the recent years. Removal of one of the two isoforms by deletion of one of the α subunits allowed the investigation of the specific functions of the respective isoform. The deletion of the β₁ subunit led to complete knock-out thus completely disrupting the NO/cGMP signaling cascade. The phenotypes of these KO mice have corroborated the already known physiological importance of the NO/cGMP cascade e.g. in the regulation of blood pressure, platelet inhibition, interneuronal communication; yet, they have also given hints to novel functions and mechanisms. In addition, mice lacking both NO-GC isoforms permitted the investigation of possible cGMP-independent signaling pathways of NO. As cell- and tissue-specific knock-out models are beginning to emerge, a more detailed analysis of the importance of the NO receptor in specific tissues will become possible.