Receptor guanylyl cyclases in mammalian olfactory function

Abstract

The contributions of guanylyl cyclases to sensory signaling in the olfactory system have been unclear. Recently, studies of a specialized subpopulation of olfactory sensory neurons (OSNs) located in the main olfactory epithelium have provided important insights into the neuronal function of one receptor guanylyl cyclase, GC-D. Mice expressing reporters such as beta-galactosidase and green fluorescent protein in OSNs that normally express GC-D have allowed investigators to identify these neurons in situ, facilitating anatomical and physiological studies of this sparse neuronal population. The specific perturbation of GC-D function in vivo has helped to resolve the role of this guanylyl cyclase in the transduction of olfactory stimuli. Similar approaches could be useful for the study of the orphan receptor GC-G, which is expressed in another distinct subpopulation of sensory neurons located in the Grueneberg ganglion. In this review, we discuss key findings that have reinvigorated the study of guanylyl cyclase function in the olfactory system.

Fig. 1

The receptor guanylyl cyclase GC-D and its role in olfactory function. a Whole-mount X-gal staining of olfactory bulbs from a Gucy2d-Mapt-lacZ ^+/− mouse shows axons of GC-D+ OSNs innervating the necklace glomeruli (blue). b Recordings of stimulus-evoked field potentials in response to MOE stimulation by uroguanylin (UG) or guanylin (G) in Cnga2, Gucy2d and Cnga3 gene-targeted mice. c–f Imaging of intracellular Ca²⁺ in an identified dendritic knob of a GC-D+ OSN: c en face view of the MOE surface, visualized with transmitted light; d Ca²⁺ signals at rest in canonical (some shown with arrowheads) and GC-D+ (arrow) OSNs; (E) GC-D+ OSN dendritic knob visualized with the fluorescent β-gal substrate resorufin galactoside; f merged image. g Examples of Ca²⁺ responses to UG (1 μM), G (1 μM) a mixture of both peptides (1 μM each) or dilute urine (1:100) in dendritic knobs from Gucy2d-Mapt-lacZ ^+/− or ^−/− mice. Panels A–G reprinted with permission from reference . Copyright 2007, National Academy of Sciences. h CO₂-dependent Ca²⁺ signals in GC-D+ OSNs are blocked by the carbonic anhydrase inhibitor acetazolamide (AZ). i Representative example of l-cis-diltiazem inhibition of CO₂-dependent Ca²⁺ signals in a GC-D+ OSN, implicating cyclic nucleotide-gated channels in the transduction of CO₂. Panels H and I reprinted with permission from reference . j Cyclase activity of rat GC-D expressed in COS-7 cells is stimulated by human uroguanylin but not rat guanylin. Reprinted with permission from reference . k A possible mechanism for the transduction of uroguanylin (or guanylin) and CO₂ by GC-D+ OSNs