STEROID REGULATION OF PEPTIDE SENSITIVITY IN THE CNS

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Steroid hormones induce long-term changes in the form and function of the nervous system. These changes are likely mediated via changes in the genome. The aim of this project is to use the steroid regulation of a peptide-mediated behavior of an insect, Manduca sexta, as a model for how steroids can control the responsiveness of the CNS. The ecdysteroids are steroid hormones which regulate the metamorphosis and molting of insects. One of the final steps in the molting process is the shedding (ecdysis) of the old cuticle. This behavior is triggered by the action of a neuropeptide, eclosion hormone (EH). The peptide can only act on the CNS, however, if the nervous system has been primed by exposure to the ecdysteroids. Studies that I have carried out indicate that the ecdysteroids act at two or more levels to regulate peptide responsiveness. Firstly on the receptor/2nd messenger (cGMP) system and secondly, inducing the de novo synthesis of two proteins (the EGPS) which are phosphorylated by the action of the peptide. Only when both of these components are functional will the nervous system respond to EH. The aim of this proposal is to examine the steroid regulation of both of these steps in detail. Using radiolabeled EH I will characterize the EH receptors and determine if they are up regulated in response to ecdysteroids. I will also elucidate the pathway by which EH elevates cGMP and ascertain if any element of this pathway is regulated by the ecdysteroids. I believe that the de novo synthesis of the EGPs is the final step in enabling the CNS to respond to EH. Once antibodies to the EGPs have been generated I will be able to follow their synthesis, the synthesis of the EGP mRNA(s) and their steroid regulation. Ultimately, I intend to isolate the steroid-regulated genes at each step in the cascade of EH action. The information gained from this proposal will be of importance to other studies in CNS plasticity which are believed to be regulated at the level of the genome.