Insects and acarines (mites, ticks) are vectors for a variety of infectious diseases (e.g., Lyme disease, malaria, equine encephalitis, Rocky Mountain spotted fever, typhus, yellow fever) in addition to being major agricultural pests. Many current pesticides and acaricides act at receptors and ion channels in the nervous systems of arthropods but, unfortunately, because they lack specificity, these pesticides also have significant side effects on the mammalian nervous system. In order to develop highly selective pesticides and acaricides, much more needs to be known about the structure and pharmacology of insect and acarine hormone and neuro-transmitter receptors, particularly those which appear from corresponding receptors in mammals. Using molecular biology techniques which have been so successful in elucidating the structure of vertebrate adrenergic receptors, this grant proposes to clone, from insects and acarines, the family of receptors for octopamine (thought to be the invertebrate analog to norepinephrine) and, subsequently, the receptor proteins for dopamine and serotonin (which may differ pharmacologically from their vertebrate counterparts). Cloning of octopamine receptors will be facilitated by recent advances in the Principal Investigator's Laboratory which have led to the development of a novel, selective, and highly potent octopamine photoaffinity ligand and the use of this ligand to purify an octopamine receptor protein. An alternative cloning strategy based upon homology to mammalian adrenergic receptors will also be used. Once isolated, the structures and pharmacology of these invertebrate amine receptors will be studied in great detail, through sequencing, site-directed mutagenesis and eukaryotic expression. The homology of these receptors to vertebrate amine receptors will be determined and the distribution of receptors and subtypes, in insects and acarines (and possibly other phylla of medical significance), will be determined for various species, tissues, and developmental stages, thereby providing a rational basis for the development of selective aminergic pesticides and acaricides.
| Scavone, C; Mckee, M; Nathanson, J A (1994) Monoamine uptake in insect synaptosomal preparations. Insect Biochem Mol Biol 24:589-97 |
| Roeder, T; Nathanson, J A (1994) Photoaffinity labeling of a neuronal octopamine receptor. J Neurochem 63:1516-21 |
| Nathanson, J A (1993) Identification of octopaminergic agonists with selectivity for octopamine receptor subtypes. J Pharmacol Exp Ther 265:509-15 |
| Roeder, T; Nathanson, J A (1993) Characterization of insect neuronal octopamine receptors (OA3 receptors). Neurochem Res 18:921-5 |
