title: Citral sensing by Transient [corrected] receptor potential channels in dorsal root ganglion neurons.
abstract: Transient receptor potential (TRP) ion channels mediate key aspects of taste, smell, pain, temperature sensation, and pheromone detection. To deepen our understanding of TRP channel physiology, we require more diverse pharmacological tools. Citral, a bioactive component of lemongrass, is commonly used as a taste enhancer, as an odorant in perfumes, and as an insect repellent. Here we report that citral activates TRP channels found in sensory neurons (TRPV1 and TRPV3, TRPM8, and TRPA1), and produces long-lasting inhibition of TRPV1-3 and TRPM8, while transiently blocking TRPV4 and TRPA1. Sustained citral inhibition is independent of internal calcium concentration, but is state-dependent, developing only after TRP channel opening. Citral's actions as a partial agonist are not due to cysteine modification of the channels nor are they a consequence of citral's stereoisoforms. The isolated aldehyde and alcohol cis and trans enantiomers (neral, nerol, geranial, and geraniol) each reproduce citral's actions. In juvenile rat dorsal root ganglion neurons, prolonged citral inhibition of native TRPV1 channels enabled the separation of TRPV2 and TRPV3 currents. We find that TRPV2 and TRPV3 channels are present in a high proportion of these neurons (94% respond to 2-aminoethyldiphenyl borate), consistent with our immunolabeling experiments and previous in situ hybridization studies. The TRPV1 activation requires residues in transmembrane segments two through four of the voltage-sensor domain, a region previously implicated in capsaicin activation of TRPV1 and analogous menthol activation of TRPM8. Citral's broad spectrum and prolonged sensory inhibition may prove more useful than capsaicin for allodynia, itch, or other types of pain involving superficial sensory nerves and skin.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Stotz
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.forename: Derek
authors.initials: D
authors.lastname: Martyn
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D000080462:Acyclic Monoterpenes; D000818:Animals; D005727:Ganglia, Spinal / Q000502:physiology*; D007700:Kinetics; D039821:Monoterpenes / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D013237:Stereoisomerism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*
chemical_list: D000080462:Acyclic Monoterpenes; D039821:Monoterpenes; D050916:TRPV Cation Channels; C505767:TRPV3 protein, rat; C493922:Trpv1 protein, rat; C476722:Trpv2 protein, rat; C486577:Trpv4 protein, rat; C007076:citral