This studies proposed here seek to elucidate the molecular mechanisms we use to sense cold. The recently cloned CMR-1 is an ion channel of the TRP family that responds to cold and small organic molecules like menthol and icilin, an after-shave component. The icilin binding site will be determined by photoaffinity labeling. This site will be held constant in a series of chimeric CMR-1 derivatives, containing fragments donated from related, but cold insensitive channels. In the resulting derivatives, sensitivitity to icilin will control for channel function while a cold sensing apparatus is located. This research expands on a growing theme in structural biology indicating that ion channel proteins have evolved in a domain specific fashion, by recombining various sets of sensors, pores, selectivity filters, and other elements and selecting for desirable traits. Success will serve to further validate this basic scientific hypothesis, contribute to an understanding of the newly appreciated field of TRP channels, and develop useful chemical tools for TRP channel manipulation. Since CMR-1 is upregulated in some carcinoma transcripts, an understanding of its gating properties may offer an opportunity in the field of cancer therapy.
