Activation of Purinergic Receptor Subtypes Modulates Odor Sensitivity

Abstract

Purinergic nucleotides, including ATP and adenosine, are important neuromodulators of peripheral auditory and visual sensory systems (Thorne and Housley, 1996). ATP released by the olfactory epithelium (OE) after noxious stimuli provides a physiological source for a neuromodulatory substance independent of efferent innervation. Here we show that multiple subtypes of purinergic receptors are differentially expressed in olfactory receptor neurons and sustentacular support cells. Activation of purinergic receptors evoked inward currents and increases in intracellular calcium in cultured mouse olfactory receptor neurons. A mouse olfactory epithelial slice preparation and confocal imaging were used to measure changes in intracellular calcium in response to odors, purinergic receptor (P2R) agonists, or combined odor + P2R agonists. Pharmacological studies show that both P2Y and P2X receptor activation by exogenous and endogenous ATP significantly reduces odor responsiveness. Moreover, purinergic receptor antagonists increase the odor-evoked calcium transient, providing direct evidence that endogenous ATP modulates odor sensitivity via activation of multiple purinergic receptor subtypes in olfactory receptor neurons. Odor activation of G-protein-coupled receptors results in increased cAMP production, opening of cyclic nucleotide-gated channels, influx of Ca2+ and Na+, depolarization of the membrane, and activation of voltage- and Ca2+-gated ion channels. On-cell current-clamp recordings of olfactory receptor neurons from neonatal mouse slices revealed that ATP reduced cyclic nucleotide-induced electrical responses. These data also support the idea that ATP modulates odor sensitivity in mammalian olfactory neurons. Peripheral ATP-mediated odor suppression is a novel mechanism for reduced olfactory sensitivity during exposure to olfactotoxins and may be a novel neuroprotective mechanism.

Cannabinoid action in the olfactory epithelium

“…First steps in this direction would be a quantification of endocannabinoid levels in the OE combined with a detailed characterization of the involved mechanisms regarding re-uptake and enzymatic hydrolysis. Our finding that the ECS influences olfactory sensory input adds to a growing knowledge showing that the activity of ORNs is modulated by numerous compounds, including acetylcholine, adrenaline, ATP, dopamine, GnRH, and s-neuropeptide Y (4,(30)(31)(32)(33)(34)(35)(36).…”

Interplay between PIP 3 and calmodulin regulation of olfactory cyclic nucleotide-gated channels

“…In contrast, inhibition of olfactory signaling by PIP 3 does not require prior channel activity, and channel regulation by PIP 3 may serve to reduce overall olfactory sensitivity in the presence of complex odorant mixtures. One possible route for PIP 3 synthesis is suggested by the recent discovery of purinergic receptors in olfactory sensory neuron membranes (43). These G protein-coupled receptors are activated by ATP and have been reported to stimulate PIP 3 synthesis in astrocytes and C6 glioma cells (44,45).…”

ATP release from non-excitable cells

“…Recent breakthroughs in this field include the role of adenosine triphosphate (ATP) as neurotransmitter and/or modulator in sensory transduction [1][2][3][4][5][6][7][8][9][10], the role of released ATP as a precursor signalling molecule in renal tubulo-glomerular feedback [11,12], the role of released nucleotides for migrating neutrophils [13] and the crucial function of nucleotides in the control of thrombocyte aggregation and haemostasis [14]. The essential features of the purinergic signalling system are well characterised.…”