Grueneberg ganglion olfactory subsystem employs a cGMP signaling pathway

Abstract

The mammalian olfactory sense employs several olfactory subsystems situated at characteristic locations in the nasal cavity to detect and report on different classes of odors. These olfactory subsystems use different neuronal signal transduction pathways, receptor expression repertoires, and axonal projection targets. The Grueneberg Ganglion (GG) is a newly-appreciated olfactory subsystem with receptor neurons located just inside of the nostrils that project axons to a unique domain of interconnected glomeruli in the caudal olfactory bulb. It is not well-understood how the GG relates to other olfactory subsystems in contributing to the olfactory sense. Furthermore, the range of chemoreceptors and the signal transduction cascade utilized by the GG have remained mysterious. To resolve these unknowns, we explored the molecular relationship between the GG and the GC-D neurons, another olfactory subsystem that innervates similarly-interconnected glomeruli in the same bulbar region. We found that mouse GG neurons express the cGMP-associated signaling proteins phosphodiesterase 2a, cGMP-dependent kinase II, and cyclic nucleotide gated channel subunit A3 coupled to a chemoreceptor repertoire of cilia-localized particulate guanylyl cyclases (pGC-G and pGC-A). The primary cGMP signaling pathway of the GG is shared with the GC-D neurons, unifying their target glomeruli as a unique center of olfactory cGMP signal transduction. However, the distinct chemoreceptor repertoire in the GG suggests that the GG is an independent olfactory subsystem. This subsystem is well-suited to detect a unique set of odors and to mediate behaviors that remained intact in previous olfactory perturbations.

Mouse alarm pheromone shares structural similarity with predator scents

“…The potential pathway(s) implicated in the detection of chemical danger cues by GG neurons remain(s) to be identified. Putative signaling elements have already been described (21,31,(54)(55)(56)(57)(58)(59), suggesting that GG neurons might use different pathways from those present in MOE or VNO neurons. Some proteins identified have a temporal pattern of expression and/or a restricted localization implying the presence of neuronal subpopulations in the GG.…”

“…From our c-Fos labeling of the olfactory bulb, we can speculate that the GG neurons activated by alarm pheromones comprise the substantial subpopulation of PDE2A-expressing neurons. Interestingly, these PDE2A-positive neurons also express in their primary cilia the particulate guanylyl cyclase pGC-G and the CNGA3 ion channels (54,57). These two membrane-bound proteins could play a role in danger cue detection.…”

Grueneberg Ganglion Neurons Are Finely Tuned Cold Sensors

“…Remarkably, mouse GGNs also express elements of a cGMP second messenger pathway, including the cGMP-specific CNGA3 channel and the cGMP-stimulated phosphodiesterase PDE2 (Fleischer et al, 2009;Liu et al, 2009). To elucidate whether cGMP signaling is necessary for cellular Ca 2ϩ responses in GGNs, we first applied the highly membrane-permeant phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 100 M) to block the breakdown of cyclic nucleotides produced by constitutive enzyme activity.…”

“…Such structures have been shown to represent primary cilia of GGNs (Brechbühl et al, 2008;Liu et al, 2009). Thus, our results provide evidence that CNGA3 resides in the GGN cilia, in accord with previous results (Liu et al, 2009). Importantly, no such immunoreactivity was observed in CNGA3-deficient GGNs (Fig.…”

“…Interestingly, these glomeruli are near the necklace glomeruli innervated by olfactory sensory neurons expressing the receptor guanylyl cyclase GC-D (Fülle et al, 1995;Juilfs et al, 1997;Leinders-Zufall et al, 2007;Walz et al, 2007; for review, see Munger et al, 2009), and both GC-D-expressing neurons and GGNs express elements of a cGMP second messenger pathway, including the cGMP-specific cyclic nucleotide-gated channel CNGA3 and the cGMP-stimulated phosphodiesterase PDE2 (Juilfs et al, 1997;Meyer et al, 2000;Leinders-Zufall et al, 2007;Fleischer et al, 2009;Liu et al, 2009). They differ, however, in the membrane-bound guanylyl cyclases they express; GGNs express guanylyl cyclase type G but not GC-D (Fleischer et al, 2009;Liu et al, 2009). …”