| Title: | Activation of pheromone-sensitive neurons is mediated by conformational activation of pheromone-binding protein |
| Author(s): | Laughlin JD; Ha TS; Jones DNM; Smith DP; |
| Address: | "Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Avenue, M/S 8303, P.O. Box 6511, Aurora CO 80045. Department of Pharmacology and Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390-9111. Program in Biomolecular Structure, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Avenue, M/S 8303, P.O. Box 6511, Aurora CO 80045" |
| DOI: | 10.1016/j.cell.2008.04.046 |
| ISSN/ISBN: | 1097-4172 (Electronic) 0092-8674 (Print) 0092-8674 (Linking) |
| Abstract: | "Detection of volatile odorants by olfactory neurons is thought to result from direct activation of seven-transmembrane odorant receptors by odor molecules. Here, we show that detection of the Drosophila pheromone, 11-cis vaccenyl acetate (cVA), is instead mediated by pheromone-induced conformational shifts in the extracellular pheromone-binding protein, LUSH. We show that LUSH undergoes a pheromone-specific conformational change that triggers the firing of pheromone-sensitive neurons. Amino acid substitutions in LUSH that are predicted to reduce or enhance the conformational shift alter sensitivity to cVA as predicted in vivo. One substitution, LUSH(D118A), produces a dominant-active LUSH protein that stimulates T1 neurons through the neuronal receptor components Or67d and SNMP in the complete absence of pheromone. Structural analysis of LUSH(D118A) reveals that it closely resembles cVA-bound LUSH. Therefore, the pheromone-binding protein is an inactive, extracellular ligand converted by pheromone molecules into an activator of pheromone-sensitive neurons and reveals a distinct paradigm for detection of odorants" |
| Keywords: | "Acetates/chemistry/metabolism Amino Acid Substitution Animals Drosophila Proteins/metabolism Drosophila melanogaster/*metabolism Female Male Models, Molecular Oleic Acids/chemistry/metabolism Olfactory Receptor Neurons/chemistry/*metabolism Pheromones/che;" |
| Notes: | "MedlineLaughlin, John D Ha, Tal Soo Jones, David N M Smith, Dean P eng R01DC02539/DC/NIDCD NIH HHS/ HHMI/Howard Hughes Medical Institute/ P30 CA046934/CA/NCI NIH HHS/ R01 AA013618/AA/NIAAA NIH HHS/ R01 DC002539/DC/NIDCD NIH HHS/ R01 DC008834/DC/NIDCD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2008/07/01 Cell. 2008 Jun 27; 133(7):1255-1265. doi: 10.1016/j.cell.2008.04.046" |
