INSECT DIURETIC HORMONES--STRUCTURES AND FUNCTION

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Insects have low pressure circulatory systems and require diuretic hormones to control production of urine by Malpighian tubules. We identified the first insect diuretic hormone (DH), Manduca sexta DH, in 1989. There are now ten members of this growing family of DH (four identified with prior funding), which are structurally homologous to the corticotropin releasing factor/sauvagine/urotensin I family of peptides. An extremely novel aspect of the sequences of the CRF-like DH is that they have homologous regions for the amino terminal half of the 30-46 residue sequence, and homology at the carboxyl terminus of the molecule but gaps are required in the middle of most sequences for good alignment of both termini. These gaps in the sequence should cause profound differences in the three dimensional conformation of the related insect DHs; curiously, all but three of the known CRF-like DH activate Malpighian tubules of Manduca sexta. We propose studies to isolate and identify CRF-like DH from Rhodnius prolixus, a vector of Chagas' disease, and two other insect species. We plan to do the work on R. prolixus in collaboration with Prof. Ian Orchard, U. of Toronto, as possession of this disease vector is strictly controlled in the US. We will also study the relative three dimensional conformation of members of this family of DH by computer modeling and by physico-chemical methods, hopefully including X-ray crystallography. We also hope to learn more about how M. sexta and DH, and other DH, interact with their receptors. We propose to determine exactly what part of the molecule activates the receptor, and to determine to what part of the receptor molecule M. sexta DH binds. Studies on this unique family of neuropeptides will provide information which may be of utility in designing small molecules with DH activity, potentially of great use for control of blood-sucking insects. Analogues of insect juvenile hormones (sesquiterpenoids) are currently in commercial use as extremely safe, specific insect control agents.