Hegg Colleen C, Greenwood Denise, Huang Wei, Han Pengcheng, Lucero Mary T
Department of Physiology, University of Utah, Salt Lake City, Utah 84108-1297, USA.
J Neurosci. 2003 Sep 10;23(23):8291-301. doi: 10.1523/JNEUROSCI.23-23-08291.2003.
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.
嘌呤能核苷酸，包括三磷酸腺苷（ATP）和腺苷，是外周听觉和视觉感觉系统重要的神经调质（索恩和豪斯利，1996年）。嗅觉上皮（OE）在有害刺激后释放的ATP为一种独立于传出神经支配的神经调质物质提供了生理来源。在此我们表明，嘌呤能受体的多种亚型在嗅觉受体神经元和支持细胞中差异表达。嘌呤能受体的激活在培养的小鼠嗅觉受体神经元中诱发内向电流并使细胞内钙增加。使用小鼠嗅觉上皮切片标本和共聚焦成像来测量对气味、嘌呤能受体（P2R）激动剂或气味+P2R激动剂组合的细胞内钙变化。药理学研究表明，外源性和内源性ATP激活P2Y和P2X受体均显著降低气味反应性。此外，嘌呤能受体拮抗剂增加气味诱发的钙瞬变，提供了直接证据表明内源性ATP通过激活嗅觉受体神经元中的多种嘌呤能受体亚型来调节气味敏感性。G蛋白偶联受体的气味激活导致环磷酸腺苷（cAMP）生成增加、环核苷酸门控通道开放、Ca2+和Na+内流、膜去极化以及电压门控和Ca2+门控离子通道激活。对新生小鼠切片的嗅觉受体神经元进行的细胞膜电流钳记录显示，ATP降低了环核苷酸诱导的电反应。这些数据也支持ATP调节哺乳动物嗅觉神经元气味敏感性的观点。外周ATP介导的气味抑制是暴露于嗅觉毒素期间嗅觉敏感性降低的一种新机制，可能是一种新的神经保护机制。
