Ingi T, Ronnett G V
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 1995 Dec;15(12):8214-22. doi: 10.1523/JNEUROSCI.15-12-08214.1995.
Recent evidence suggests that, like nitric oxide (NO), carbon monoxide (CO), another activator of soluble guanylyl cyclase, may serve as an intercellular messenger in the brain. Heme oxygenase, which converts heme to biliverdin and CO, is abundantly expressed in the brain and is localized to discrete neuronal populations. However, evidence for the actual generation of CO by neurons is lacking. Heme oxygenase-2 immunoreactivity is abundantly present in olfactory receptor neurons where it essentially colocalizes with immunoreactivity to soluble guanylyl cyclase, the target of CO action. To examine the generation of CO by neurons, we measured CO production directly and determined its relationship to cyclic GMP levels in cultured rat olfactory receptor neurons. This system has the advantage of not having measurable NO production, which could confound results since NO is a more potent activator of guanylyl cyclase than CO. Metabolic labeling experiments permitted the direct measurement of 14CO production by neurons in vitro. CO release parallels endogenous cyclic GMP concentrations with its peak at the immature stage of neuronal differentiation in culture. Cyclic GMP production is inhibited by zinc protoporphyrin-9 and zinc deuteroporphyrin IX 2,4-bis glycol, inhibitors of heme oxygenase, indicating that CO is an endogenous regulator of soluble guanylyl cyclase activities in these cells. Transforming growth factor-beta 2, an olfactory neurogenic factor, specifically shows a negative effect on CO release in olfactory receptor neurons. These results indicate that CO may serve as a gaseous neuronal messenger linked to cyclic GMP production and suggests its involvement in developmental processes of the olfactory receptor neuron.
最近的证据表明，与一氧化氮（NO）一样，可溶性鸟苷酸环化酶的另一种激活剂一氧化碳（CO）可能在大脑中充当细胞间信使。血红素加氧酶可将血红素转化为胆绿素和CO，在大脑中大量表达，并定位于离散的神经元群体。然而，缺乏神经元实际产生CO的证据。血红素加氧酶-2免疫反应性大量存在于嗅觉受体神经元中，它基本上与可溶性鸟苷酸环化酶（CO作用的靶点）的免疫反应性共定位。为了研究神经元产生CO的情况，我们直接测量了CO的产生，并确定了其与培养的大鼠嗅觉受体神经元中环状GMP水平的关系。该系统的优点是没有可测量的NO产生，因为NO是比CO更有效的鸟苷酸环化酶激活剂，可能会混淆结果。代谢标记实验允许直接测量体外神经元产生的14CO。CO的释放与内源性环状GMP浓度平行，在培养的神经元分化的未成熟阶段达到峰值。环状GMP的产生受到锌原卟啉-9和锌中卟啉IX 2,4-双二醇（血红素加氧酶抑制剂）的抑制，表明CO是这些细胞中可溶性鸟苷酸环化酶活性的内源性调节剂。转化生长因子-β2是一种嗅觉神经发生因子，对嗅觉受体神经元中的CO释放有特异性的负面影响。这些结果表明，CO可能作为一种与环状GMP产生相关的气态神经元信使，并提示其参与嗅觉受体神经元的发育过程。
