| Description |
Constellation pharmacology is an imaging platform that can be used to identify functionally relevant cell-types based on cell-specific combinations (constellations) of key signaling proteins, and to screen for novel pharmacological agents that target these proteins and cell-types. In this dissertation, cold-sensitive somatosensory neurons expressing TRPM8 and TRPA1 channels were identified and studied from rodent dorsal root ganglia and trigeminal ganglia. We have identified constellations of ion channels functionally expressed in TRPM8- and TRPA1-expressing neurons, which has provided novel insight into the role of these neurons in cold sensation. Our results are consistent with the model where TRPM8-expressing neurons contribute to innocuous cold-sensation and cold-sensitive TRPA1-expressing neurons contribute to noxious cold-sensation. Using constellation pharmacology, we also identified the cellular and molecular target of sweet and licorice fennel oil and its major active compound trans-anethole. To our surprise, both fennel oil and trans-anethole selectively target TRPA1-expressing neurons in mouse somatosensory neurons. Furthermore, both fennel oil and trans-anethole also activate human TRPA1 channels. Hence, this dissertation is a good case study for how constellation pharmacology can be used for cell-type identification and screening natural products for discovery. |
