Many changes in the properties of the nervous system are brought about by chemical messengers such as neurotransmitters and neuromodulators. These frequently exert their effects by acting on cell surface receptors to change the concentrations of additional chemical messengers inside the cell. There are probably hundreds of different types of neurotransmitters and neuromodulators whereas there are only a handful of chemicals which have been identified as intracellular messengers and include cyclic AMP (cAMP), calcium, inositol (1,4,5) trisphosphate (InsP3) and cyclic GMP (cGMP). Many previous studies have highlighted the importance of cAMP, calcium and InsP3 in the function and plasticity of the nervous system. A number of important therapeutic drugs have been shown to exert their effects by interfering with these intracellular messenger cascades, such as lithium used for the treatment of bipolar disorder. By contrast, the regulation and functions of another intracellular messenger, cGMP, has received relatively little attention. This lab has been using the nervous system of the insect, Manduca sexta, as a model for cGMP regulation and function for several years and the applicants have shown that a behaviorally relevant neuropeptide, eclosion hormone (EH) exerts it effects by stimulating an increase in the cGMP levels in the nervous system of Manduca. The investigators have evidence to suggest that the peptide-stimulated increase in cGMP is mediated by additional messengers, possibly lipids, and one site of action of EH are the neurosecretory terminals in a neurohemal organ. This proposal aims to build on these observations to study, in more detail, the mechanisms involved in the increase in cGMP and to investigate possible functions for the increase in cGMP in neurosecretory terminals. The investigators have cloned several isoforms of the enzyme responsible for the synthesis of cGMP, guanylyl cyclase and intend to investigate their regulation and location in the CNS of Manduca. In particular, they will study the potential role of lipid messengers in the regulation of the guanylyl cyclases and which of the cyclases are expressed in the neurosecretory terminals where EH acts. EH stimulates an increase of cGMP in the neurosecretory terminals and they also intend to determine if this increase in cGMP regulates the release of neurohormones from these terminals. These studies will greatly increase our knowledge of the regulation and function of this relatively little studied messenger.
