Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium

<jats:p> 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 <jats:italic>Gucy2d</jats:italic> , which encodes GC-D, with patch clamp recording and confocal Ca <jats:sup>2+</jats:sup> imaging from single dendritic knobs <jats:italic>in situ</jats:italic> , 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 Ca <jats:sup>2+</jats:sup> and action potential firing. Responses are eliminated in both <jats:italic>Gucy2d</jats:italic> - and <jats:italic>Cnga3</jats:italic> -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. </jats:p>