The cGMP signaling system has been implicated in several disorders, suggesting great potential as a target for new effective pharmacological therapies. Dysfunctions of the cGMP signaling cascade at various levels have been implicated in cardiovascular disease (arterial hypertension, cardiac hypertrophy, metabolic syndrome), neurodegenerative disorders (retinal degeneration, Alzheimer’s disease), movement disorders (Parkinson’s and Huntington’s disease), muscle disease (Duchenne’s muscular dystrophy), autism, bipolar disorders, schizophrenia, and skeletal deformities. The critical role of the NO-GC and natriuretic peptide/GC-A systems in the regulation of arterial blood pressure has been known for a long time. Importantly, recent studies illustrated that even subtle changes due to genetic variants in components of this pathway (e.g. NO-GC, ANP, BNP; PDEs) significantly influence blood pressure and cardiovascular disease risk in humans. Interestingly, genetic mutations in NO-GC or cGKI found in humans are causally associated with altered vascular structure and remodeling.
Novel functions of cGMP and clinical applications of cGMP-based drugs are continuously being discovered. For instance, CNP/GC-B maintains meiotic arrest in mouse oocytes and intercellular cGMP diffusion through gap junctions in ovarian follicles restarts meiosis. The GC-C receptor, previously thought to be exclusively expressed in the intestine, has been detected in the brain and plays a major role in feeding behavior as well as in attention deficiency and hyperactive behavior. Presynaptically localized cGKI was shown to be a key determinant of spinal synaptic potentiation and pain hypersensitivity. PDE9A may be a new druggable target to increase cGMP pools in the heart that are predominantly controlled by ANP/GC-A. Recent collaborative work of investigators of the proposed consortium has shown that cGMP/cGKI signaling and PDE5 inhibition protect cochlear hair cells and hearing function after noise-induced trauma.
Taken together, the available preclinical and clinical evidence demonstrates that the cGMP signaling pathway has a strong impact on human physiology and pathophysiology, and that it is an attractive drug target to tackle an array of major human diseases.
Although our general knowledge about formation of cGMP, its effector molecules, and cellular functions has substantially increased in the last several years, critical gaps remain. Gaps mostly concern the mechanisms and consequences of cGMP compartmentation, and the molecular pathways that mediate the positive and negative effects of cGMP on health and disease. Answers to these questions are needed to understand and potentially improve the increasing clinical use of cGMP-modulating drugs. In this GRK, investigators from different disciplines will share expert knowledge about cGMP signaling, cancer, the cardiovascular and nervous systems, unique genetic mouse models, and sophisticated optical and functional methods to elucidate novel cGMP roles and regulators.