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BIOLOGICAL SCIENCES / NEUROSCIENCE
Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium

Trese Leinders-Zufall^*, Renee E. Cockerham, Stylianos Michalakis, Martin Biel, David L. Garbers, Randall R. Reed^¶, Frank Zufall^*,||, and Steven D. Munger^,**

*Department of Physiology, University of Saarland School of Medicine, 66421 Homburg/Saar, Germany; Department of Anatomy and Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201; Munich Center for Integrated Protein Science and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; Department of Pharmacology and the Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390; and ^¶Department of Molecular Biology and Genetics and Center for Sensory Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205

Edited by Linda B. Buck, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved July 26, 2007 (received for review May 25, 2007)

The mammalian main olfactory epithelium (MOE) recognizes and transduces olfactory cues through a G protein-coupled, cAMP-dependent signaling cascade. Additional chemosensory transduction mechanisms have been suggested but remain controversial. We show that a subset of MOE neurons expressing the orphan receptor guanylyl cyclase GC-D and the cyclic nucleotide-gated channel subunit CNGA3 employ an excitatory cGMP-dependent transduction mechanism for chemodetection. By combining gene targeting of Gucy2d, which encodes GC-D, with patch clamp recording and confocal Ca²⁺ imaging from single dendritic knobs in situ, we find that GC-D cells recognize the peptide hormones uroguanylin and guanylin as well as natural urine stimuli. These molecules stimulate an excitatory, cGMP-dependent signaling cascade that increases intracellular Ca²⁺ and action potential firing. Responses are eliminated in both Gucy2d- and Cnga3-null mice, demonstrating the essential role of GC-D and CNGA3 in the transduction of these molecules. The sensitive and selective detection of two important natriuretic peptides by the GC-D neurons suggests the possibility that these cells contribute to the maintenance of salt and water homeostasis or the detection of cues related to hunger, satiety, or thirst.

cGMP | natriuretic peptide | transduction | Gucy2d | CNGA3

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0704965104/DC1.

^||To whom correspondence may be addressed. E-mail: frank.zufall{at}uks.eu

**To whom correspondence may be addressed at: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn Street, S251, Baltimore, MD 21201. E-mail: smung001{at}umaryland.edu

© 2007 by The National Academy of Sciences of the USA

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