To respond appropriately to its dynamic environment, a sensory neuron must attenuate its response to persistent stimuli while remaining sensitive to a novel stimulus. This is accomplished by specifically turning down or adapting, the response of the receptor. Accurate adaptation of signaling events is crucial throughout the nervous system; failure to down-regulate the G-protein coupled receptor (GPCR) rhodopsin signaling leads to retinal degeneration and blindness in Oguchi disease (Chen et al., 1999) while hyperadaptation of the mu opioid GPCR signaling by morphine leads to tolerance associated with opiate addiction (Whistler et al., 1998). Though the initial signal transduction events and rapid turn off of such GPCR-mediated signaling are well described, little is known about how these neurons adapt to prolonged stimulation. In this grant, we propose to identify the molecules and molecular processes responsible for long lasting adaptation of GPCR signaling in C. elegans. Study of a model organism that is tractable to both genetics and cell biology affords us the opportunity to examine the molecular processes that deactivate odor signaling. We will use cell biological techniques to examine the initiation of long-term adaptation by the PKG, EGL-4. In so doing, we will characterize the role that such basic biological processes as transcription, and endocytosis play in promoting adaptation. Finally, we will identify new molecules required to initiate adaptation of a GPCR signaling. Biophysical, biochemical, and protein trafficking changes that regulate adaptation in C. elegans sensory neurons are likely to have their counterparts in the mammalian central nervous system. The genes identified as being important for initiating long-term adaptation are likely to have conserved functions in diverse cell types that rely on adaptation-like processes to respond to prolonged or repeated signaling.
