High-affinity olfactory receptor for the death-associated odor cadaverine

Edited by Cornelia I. Bargmann, The Rockefeller University, New York, NY, and approved October 18, 2013 (received for review October 2, 2013)
November 11, 2013
110 (48) 19579-19584

Significance

Cadaverine and putrescine, two diamines emanating from decaying flesh, are strongly repulsive odors to humans but serve as innate attractive or social cues in other species. Here we show that zebrafish, a vertebrate model system, exhibit powerful and innate avoidance behavior to both diamines, and identify a high-affinity olfactory receptor for cadaverine.

Abstract

Carrion smell is strongly repugnant to humans and triggers distinct innate behaviors in many other species. This smell is mainly carried by two small aliphatic diamines, putrescine and cadaverine, which are generated by bacterial decarboxylation of the basic amino acids ornithine and lysine. Depending on the species, these diamines may also serve as feeding attractants, oviposition attractants, or social cues. Behavioral responses to diamines have not been investigated in zebrafish, a powerful model system for studying vertebrate olfaction. Furthermore, olfactory receptors that detect cadaverine and putrescine have not been identified in any species so far. Here, we show robust olfactory-mediated avoidance behavior of zebrafish to cadaverine and related diamines, and concomitant activation of sparse olfactory sensory neurons by these diamines. The large majority of neurons activated by low concentrations of cadaverine expresses a particular olfactory receptor, trace amine-associated receptor 13c (TAAR13c). Structure-activity analysis indicates TAAR13c to be a general diamine sensor, with pronounced selectivity for odd chains of medium length. This receptor can also be activated by decaying fish extracts, a physiologically relevant source of diamines. The identification of a sensitive zebrafish olfactory receptor for these diamines provides a molecular basis for studying neural circuits connecting sensation, perception, and innate behavior.

Continue Reading

Acknowledgments

We thank Walter Nadler for help with programming; Yuichiro Oka for critical review of the manuscript; Wayne Korzan, Matthias Gruhn, and Kim Korsching for technical advice; Jamie Lemon and Priyanka Maity for technical support; and Ansgar Bueschges for housing our behavioral set-up. This work was supported by Deutsche Forschungsgemeinschaft Award KO-1046/3 (to S.I.K.); an International Graduate School in Genetics and Functional Genomics stipend (to A.H. and L.R.S.); an International Graduate School in Development Health and Disease stipend (to G.A.); a Boehringer Ingelheim travel grant (to L.R.S.); and a grant (Award Number R01DC010155) from the National Institute on Deafness and Other Communicative Disorders (to S.D.L.).

Supporting Information

Supporting Information (PDF)
Supporting Information

References

1
VR Heale, K Petersen, CH Vanderwolf, Effect of colchicine-induced cell loss in the dentate gyrus and Ammon’s horn on the olfactory control of feeding in rats. Brain Res 712, 213–220 (1996).
2
SH Rolen, PW Sorensen, D Mattson, J Caprio, Polyamines as olfactory stimuli in the goldfish Carassius auratus. J Exp Biol 206, 1683–1696 (2003).
3
K Hamana, S Matsuzaki, Unusual polyamines in slime molds Physarum polycephalum and Dictyostelium discoideum. J Biochem 95, 1105–1110 (1984).
4
BV Burger, et al., Chemical characterization of territorial marking fluid of male Bengal tiger, Panthera tigris. J Chem Ecol 34, 659–671 (2008).
5
JP Pinel, BB Gorzalka, F Ladak, Cadaverine and putrescine initiate the burial of dead conspecifics by rats. Physiol Behav 27, 819–824 (1981).
6
WC Michel, MJ Sanderson, JK Olson, DL Lipschitz, Evidence of a novel transduction pathway mediating detection of polyamines by the zebrafish olfactory system. J Exp Biol 206, 1697–1706 (2003).
7
K Nara, LR Saraiva, X Ye, LB Buck, A large-scale analysis of odor coding in the olfactory epithelium. J Neurosci 31, 9179–9191 (2011).
8
R Pacifico, A Dewan, D Cawley, C Guo, T Bozza, An olfactory subsystem that mediates high-sensitivity detection of volatile amines. Cell Rep 2, 76–88 (2012).
9
Y Yoshihara, Molecular genetic dissection of the zebrafish olfactory system. Results Probl Cell Differ 47, 97–120 (2009).
10
GJ Lieschke, PD Currie, Animal models of human disease: Zebrafish swim into view. Nat Rev Genet 8, 353–367 (2007).
11
G Gerlach, J Atema, MJ Kingsford, KP Black, V Miller-Sims, Smelling home can prevent dispersal of reef fish larvae. Proc Natl Acad Sci USA 104, 858–863 (2007).
12
KM Guthrie, AJ Anderson, M Leon, C Gall, Odor-induced increases in c-fos mRNA expression reveal an anatomical “unit” for odor processing in olfactory bulb. Proc Natl Acad Sci USA 90, 3329–3333 (1993).
13
JM Mirich, KR Illig, PC Brunjes, Experience-dependent activation of extracellular signal-related kinase (ERK) in the olfactory bulb. J Comp Neurol 479, 234–241 (2004).
14
F Weth, W Nadler, S Korsching, Nested expression domains for odorant receptors in zebrafish olfactory epithelium. Proc Natl Acad Sci USA 93, 13321–13326 (1996).
15
Y Sato, N Miyasaka, Y Yoshihara, Hierarchical regulation of odorant receptor gene choice and subsequent axonal projection of olfactory sensory neurons in zebrafish. J Neurosci 27, 1606–1615 (2007).
16
SD Liberles, LB Buck, A second class of chemosensory receptors in the olfactory epithelium. Nature 442, 645–650 (2006).
17
A Hussain, LR Saraiva, SI Korsching, Positive Darwinian selection and the birth of an olfactory receptor clade in teleosts. Proc Natl Acad Sci USA 106, 4313–4318 (2009).
18
DM Ferrero, et al., Agonists for 13 trace amine-associated receptors provide insight into the molecular basis of odor selectivity. ACS Chem Biol 7, 1184–1189 (2012).
19
DM Ferrero, et al., Detection and avoidance of a carnivore odor by prey. Proc Natl Acad Sci USA 108, 11235–11240 (2011).
20
Q Li, et al., Synchronous evolution of an odor biosynthesis pathway and behavioral response. Curr Biol 23, 11–20 (2013).
21
ES Huang, Construction of a sequence motif characteristic of aminergic G protein-coupled receptors. Protein Sci 12, 1360–1367 (2003).
22
JL Mietz, E Karmas, Polyamine and histamine content of rockfish, salmon, lobster, and shrimp as an indicator of decomposition. J Assoc Off Anal Chem 61, 139–145 (1978).
23
K Mori, H Sakano, How is the olfactory map formed and interpreted in the mammalian brain? Annu Rev Neurosci 34, 467–499 (2011).
24
DJ Speca, et al., Functional identification of a goldfish odorant receptor. Neuron 23, 487–498 (1999).
25
S Demaria, et al., Role of a ubiquitously expressed receptor in the vertebrate olfactory system. J Neurosci 33, 15235–15247 (2013).
26
SH Fuss, SI Korsching, Odorant feature detection: Activity mapping of structure response relationships in the zebrafish olfactory bulb. J Neurosci 21, 8396–8407 (2001).
27
H Saito, Q Chi, H Zhuang, H Matsunami, JD Mainland, Odor coding by a mammalian receptor repertoire. Sci Signal 2, ra9 (2009).
28
P Mombaerts, Genes and ligands for odorant, vomeronasal and taste receptors. Nat Rev Neurosci 5, 263–278 (2004).
29
Y Oka, et al., Odorant receptor map in the mouse olfactory bulb: In vivo sensitivity and specificity of receptor-defined glomeruli. Neuron 52, 857–869 (2006).
30
D Krautwurst, KW Yau, RR Reed, Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell 95, 917–926 (1998).
31
RW Friedrich, SI Korsching, Combinatorial and chemotopic odorant coding in the zebrafish olfactory bulb visualized by optical imaging. Neuron 18, 737–752 (1997).
32
K Kobayakawa, et al., Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007).
33
SC Mitchell, RL Smith, Trimethylaminuria: The fish malodor syndrome. Drug Metab Dispos 29, 517–521 (2001).
34
G Ahuja, et al., Zebrafish crypt neurons project to a single, identified mediodorsal glomerulus. Sci Rep 3, 2063 (2013).
35
Y Oka, LR Saraiva, SI Korsching, Crypt neurons express a single V1R-related ora gene. Chem Senses 37, 219–227 (2012).

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 110 | No. 48
November 26, 2013
PubMed: 24218586

Classifications

Submission history

Published online: November 11, 2013
Published in issue: November 26, 2013

Keywords

  1. Danio rerio
  2. aversion
  3. heterologous expression
  4. polyamines

Acknowledgments

We thank Walter Nadler for help with programming; Yuichiro Oka for critical review of the manuscript; Wayne Korzan, Matthias Gruhn, and Kim Korsching for technical advice; Jamie Lemon and Priyanka Maity for technical support; and Ansgar Bueschges for housing our behavioral set-up. This work was supported by Deutsche Forschungsgemeinschaft Award KO-1046/3 (to S.I.K.); an International Graduate School in Genetics and Functional Genomics stipend (to A.H. and L.R.S.); an International Graduate School in Development Health and Disease stipend (to G.A.); a Boehringer Ingelheim travel grant (to L.R.S.); and a grant (Award Number R01DC010155) from the National Institute on Deafness and Other Communicative Disorders (to S.D.L.).

Notes

*This Direct Submission article had a prearranged editor.

Authors

Affiliations

Ashiq Hussain2
Institut für Genetik, Universität zu Köln, 50674 Cologne, Germany; and
Present address: Department of Molecules, Signaling, and Development, Max-Planck-Institut für Neurobiologie, 82152 Martinsried, Germany.
Luis R. Saraiva2
Institut für Genetik, Universität zu Köln, 50674 Cologne, Germany; and
Present address: European Molecular Biology Laboratory–European Bioinformatics Institute (EMBL–EBI) and Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton-Cambridge CB10 1SD, United Kingdom.
David M. Ferrero2
Department of Cell Biology, Harvard University, Boston, MA 02115
Gaurav Ahuja2
Institut für Genetik, Universität zu Köln, 50674 Cologne, Germany; and
Venkatesh S. Krishna
Institut für Genetik, Universität zu Köln, 50674 Cologne, Germany; and
Stephen D. Liberles4 [email protected]
Department of Cell Biology, Harvard University, Boston, MA 02115
Sigrun I. Korsching4 [email protected]
Institut für Genetik, Universität zu Köln, 50674 Cologne, Germany; and

Notes

4
To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: S.D.L. and S.I.K. designed research; A.H., L.R.S., D.M.F., G.A., and V.S.K. performed research; A.H., S.D.L., and S.I.K. analyzed data; and A.H., L.R.S., G.A., S.D.L., and S.I.K. wrote the paper.
2
A.H., L.R.S., D.M.F., and G.A. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

Metrics & Citations

Metrics

Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to ths delay, usage data will not appear immediately following publication. Citation information is sourced from Crossref Cited-by service.


Citation statements

Altmetrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

Cited by

    Loading...

    View Options

    View options

    PDF format

    Download this article as a PDF file

    DOWNLOAD PDF

    Get Access

    Login options

    Check if you have access through your login credentials or your institution to get full access on this article.

    Personal login Institutional Login

    Recommend to a librarian

    Recommend PNAS to a Librarian

    Purchase options

    Purchase this article to access the full text.

    Single Article Purchase

    High-affinity olfactory receptor for the death-associated odor cadaverine
    Proceedings of the National Academy of Sciences
    • Vol. 110
    • No. 48
    • pp. 19175-19651

    Media

    Figures

    Tables

    Other

    Share

    Share

    Share article link

    Share on social media