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David Morton Laboratory

Summary:

My lab is primarily interested in intracellular signaling pathways in the nervous system with a specific focus on the messenger, cyclic GMP. Cyclic GMP has been shown to regulate diverse physiological functions including phototransduction, smooth muscle tone, water balance and ion fluxes and neuronal plasticity. Cyclic GMP is synthesized by the enzyme guanylyl cyclase (GC) of which there are two major families: cytoplasmically localized soluble GCs (sGCs) and membrane associated receptor GCs (rGCs). Activation of these enzymes, and hence an increase in cellular cyclic GMP concentrations, is achieved by two very different mechanisms. Soluble GCs are heterodimeric proteins that bind a heme prosthetic group and can be activated by free radical messengers such as the gas nitric oxide (NO) that can act as both an intra- and inter-cellular messenger. Receptor GCs, by contrast, are activated by extracellular ligands - usually peptide hormones - by binding to the extracellular portion of the protein.

We have been using an insect, Manduca sexta, for several years as a model for cyclic GMP function and have shown that a neuropeptide, eclosion hormone, elevates cyclic GMP in a neurohemal organ associated with the nervous system. As part of our efforts to elucidate the pathway by which eclosion hormone elevates cyclic GMP we have cloned several different GCs from the CNS of Manduca. In addition to examples of both classic sGCs and rGCs we have also cloned two novel GCs, which don't fit into the usual classification. One of these, MsGC-b3, is closely related to NO-sensitive heterodimeric sGCs, but we have shown that it does not need to form a heterodimer to synthesize cyclic GMP and is insensitive to NO. The other novel GC, MsGC-I, is most closely related to rGCs, but lacks an extracellular ligand-binding domain and hence cannot be activated by extracellular hormones. Our current research is aimed at understanding the regulation and function of these novel signal transduction enzymes.

Recently, we have also begun to use two new model systems, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, to study GC function and regulation. The published sequence of the C. elegans genome reveals that it has 7 sGCs, yet no NO synthase, suggesting that it cannot use this messenger to activate cGMP production. The Drosophila genome also contains several novel GCs including one that is likely to be the homologue of MsGC-b3. By using genetic manipulations in these organisms we hope to understand how this novel signaling pathway is regulated and what physiological functions it serves.

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Last updated: 2013-02-04T14:29:38.392-06:00

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