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The Journal of Neuroscience, June 18, 2008, 28(25):6407-6418; doi:10.1523/JNEUROSCI.1425-08.2008

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Cellular/Molecular
Sulfated Steroids as Natural Ligands of Mouse Pheromone-Sensing Neurons

Francesco Nodari,¹ Fong-Fu Hsu,² Xiaoyan Fu,¹ Terrence F. Holekamp,¹ Lung-Fa Kao,³ John Turk,² and Timothy E. Holy¹

Departments of ¹Anatomy and Neurobiology and ²Internal Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri 63110, and ³Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri 63130

Correspondence should be addressed to Timothy E. Holy, 660 South Euclid Avenue, Campus Box 8108, St. Louis, MO 63110. Email: holy{at}wustl.edu

Among mice, pheromones and other social odor cues convey information about sex, social status, and identity; however, the molecular nature of these cues is essentially unknown. To identify these cues, we screened chromatographic fractions of female mouse urine for their ability to cause reproducible firing rate increases in the pheromone-detecting vomeronasal sensory neurons (VSNs) using multielectrode array (MEA) recording. Active compounds were found to be remarkably homogenous in their basic properties, with most being of low molecular weight, moderate hydrophobicity, low volatility, and possessing a negative electric charge. Purification and structural analysis of active compounds revealed multiple sulfated steroids, of which two were identified as sulfated glucocorticoids, including corticosterone 21-sulfate. Sulfatase-treated urine extracts lost >80% of their activity, indicating that sulfated compounds are the predominant VSN ligands in female mouse urine. As measured by MEA recording, a collection of 31 synthetic sulfated steroids triggered responses 30-fold more frequently than did a similarly sized stimulus set containing the majority of all previously reported VSN ligands. Collectively, VSNs detected all major classes of sulfated steroids, but individual neurons were sensitive to small variations in chemical structure. VSNs from both males and females detected sulfated steroids, but knock-outs for the sensory transduction channel TRPC2 did not detect these compounds. Urine concentrations of the two sulfated glucocorticoids increased many fold in stressed animals, indicating that information about physiological status is encoded by the urine concentration of particular sulfated steroids. These results provide an unprecedented characterization of the signals available for chemical communication among mice.

Key words: vomeronasal; olfactory; glucocorticoids; stress; tuning; multielectrode array

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Received April 3, 2008; revised May 2, 2008; accepted May 5, 2008.

Correspondence should be addressed to Timothy E. Holy, 660 South Euclid Avenue, Campus Box 8108, St. Louis, MO 63110. Email: holy{at}wustl.edu

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