The broad long-term objective of this research is to elucidate the molecular mechanisms underlying sensitivity to the Drosophila male-specific volatile pheromone, 11-cis vaccenyl acetate (cVA). This work is significant because understanding pheromone signal transduction in Drosophila will translate into new methods to control reproduction in insects that transmit human diseases and destroy crops. In the last funding cycle, we made significant progress toward elucidating the mechanisms underlying cVA perception. We discovered a unique signaling paradigm in which activation of pheromone-sensitive neurons is mediated by conformational activation of the extracellular odorant binding protein, LUSH. We have identified several of the proteins that are components of the neuronal receptor complex triggered by activated LUSH, including Or67d, a member of the Drosophila odorant receptor family, and SNMP, a Drosophila homolog of CD36, a membrane protein implicated in atherosclerosis and dyslipidemia in humans. We also found four new gene products essential for normal pheromone detection in a forward genetic screen. In the next funding cycle, we are poised to make rapid progress by exploring how these factors mediate cVA sensitivity. We propose a multidisciplinary approach that includes genetics, electrophysiology, biochemistry, cell and structural biology.
The first aim i s to further define what activated LUSH interacts with on the T1 dendrites in the pheromone detection cascade. We will also initiate experiments to understand how a single amino-acid mutation in Or67d eliminates signaling.
The second aim i s to establish if the conformational activation mechanism we have uncovered for LUSH is conserved for other OBPs.
The third aim i s to define the roles of four new cVA sensitivity factors, odd, vans, vainsB and vainsE identified in the forward genetic screen.
Aim 4 is to identify the components required for cVA signal detection mapping to the second chromosome, bringing us closer to our overall goal of identifying the complete set of gene products important for cVA sensitivity. The completion of the studies outlined here will advance our understanding of volatile pheromone signaling in insects, will identify new targets to manipulate insect behavior, and will guide future studies on pheromone signaling in more complex animal model systems.

Public Health Relevance

Insects carry human diseases that kill millions of people every year;malaria alone accounts for over one million deaths annually. Insects also impact agriculture, destroying billions of dollars worth of crops annually. Many insect behaviors, including mating, are triggered by perception of pheromones. Understanding how pheromones are detected at the molecular level will provide new targets to manipulate pheromone communication, with the long-term goal of blocking mating signals and other pheromone-guided behaviors in pathogenic insects. We have identified several genes essential for volatile pheromone detection in Drosophila and will elucidate the roles of these factors in pheromone detection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC002539-18
Application #
8513292
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
1995-08-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
18
Fiscal Year
2013
Total Cost
$303,732
Indirect Cost
$110,272
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ha, Tal Soo; Xia, Ruohan; Zhang, Haiying et al. (2014) Lipid flippase modulates olfactory receptor expression and odorant sensitivity in Drosophila. Proc Natl Acad Sci U S A 111:7831-6
Lvovskaya, Svetlana; Smith, Dean P (2013) A spoonful of bitter helps the sugar response go down. Neuron 79:612-4
Kwon, Young; Kim, Sang Hoon; Ronderos, David S et al. (2010) Drosophila TRPA1 channel is required to avoid the naturally occurring insect repellent citronellal. Curr Biol 20:1672-8
Laughlin, John D; Ha, Tal Soo; Jones, David N M et al. (2008) Activation of pheromone-sensitive neurons is mediated by conformational activation of pheromone-binding protein. Cell 133:1255-65
Jin, Xin; Ha, Tal Soo; Smith, Dean P (2008) SNMP is a signaling component required for pheromone sensitivity in Drosophila. Proc Natl Acad Sci U S A 105:10996-1001
Ha, Tal Soo; Smith, Dean P (2006) A pheromone receptor mediates 11-cis-vaccenyl acetate-induced responses in Drosophila. J Neurosci 26:8727-33
Elmore, Tamara; Ignell, Rickard; Carlson, John R et al. (2003) Targeted mutation of a Drosophila odor receptor defines receptor requirement in a novel class of sensillum. J Neurosci 23:9906-12
Liu, Qinghua; Rand, Tim A; Kalidas, Savitha et al. (2003) R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway. Science 301:1921-5
Xu, P X; Zwiebel, L J; Smith, D P (2003) Identification of a distinct family of genes encoding atypical odorant-binding proteins in the malaria vector mosquito, Anopheles gambiae. Insect Mol Biol 12:549-60
Kalidas, Savitha; Smith, Dean P (2002) Novel genomic cDNA hybrids produce effective RNA interference in adult Drosophila. Neuron 33:177-84

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