The long-term goal of this project is to understand how the properties of neurons are modulated by changes in oxygen concentration and cyclic GMP (cGMP). The intracellular messenger, cyclic GMP (cGMP), is a mediator of many physiological processes including vascular tone, kidney function, neural plasticity, cardiac muscle contractility and photoreceptor function. The levels of cGMP in a cell are regulated by a balance of its synthesis, by guanylyl cyclases (GCs), and its degradation, by phosphodiesterases. This project is aimed at increasing our understanding of the regulation and function of cGMP in the nervous system, focusing on a newly identified class of atypical soluble GCs (sGCs). Conventional sGCs are the primary targets for nitric oxide (NO). The atypical sGCs are poorly activated by NO. Examples are widespread, occuring in mammals and invertebrates such as insects and nematodes. Several lines of evidence strongly support the hypothesis that at least some examples of these atypical sGCs are molecular oxygen sensors. We plan to use the fruit fly, Drosophila melanogaster as a model to investigate the function and regulation of atypical sGCs and to test the hypothesis that they act as oxygen sensors providing information to the organism of the local oxygen concentration. Biochemical techniques will be used to directly assess the interaction of oxygen with the enzymes and physiological and behavioral analysis will examine the properties of the sensory neurons that express these sGCs to determine whether they act as oxygen sensors and mediate behavioral responses to hypoxia. One of the strengths of using Drosophila as a model system is the relative ease with which genetic manipulations can be carried out to modify the expression of the sGCs and a variety of exogenous gene products. The short-term and long-term physiological consequences of hypoxia in mammals are well known, however, the nature of the molecular oxygen sensor is still somewhat unclear. Our results will provide new information to understand how animals sense hypoxia. The results from this study will provide new insights and understanding of the cGMP pathway. The diversity of this signaling system is only now being, appreciated and the pharmaceutical industry is active in developing new compounds that specifically target cGMP regulation. These compounds promise to address a wide variety of health disorders including cardiovascular, urinary and neurological problems. Viagra and other pharmacological treatments for erectile disfunction are probably just the tip of the iceberg for compounds that target cGMP mediated processes. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Stewart, Randall R
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Oregon Health and Science University
Schools of Dentistry
United States
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Brown, Kim M; Day, Jon P; Huston, Elaine et al. (2013) Phosphodiesterase-8A binds to and regulates Raf-1 kinase. Proc Natl Acad Sci U S A 110:E1533-42
Vermehren-Schmaedick, Anke; Scudder, Charles; Timmermans, Wendy et al. (2011) Drosophila gustatory preference behaviors require the atypical soluble guanylyl cyclases. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 197:717-27
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