Molecular components of signal amplification in olfactory sensory cilia
Molecular components of signal amplification in olfactory sensory cilia
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DOI：
10.1073/pnas.0909032107
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发表时间：
2010-03-30
影响因子：
11.1
通讯作者：
Moehrlen, Frank
中科院分区：
文献类型：
--
作者：
Hengl, Thomas;Kaneko, Hiroshi;Moehrlen, Frank
哺乳动物的嗅觉系统用一组有限的气味感受器来检测无限种类的气味。为了应对气味世界的复杂性，每个气味感受器必须检测许多不同的气味。对低气味选择性的需求给转导过程带来了问题：最初的转导步骤，即第二信使cAMP的合成，效率很低，主要是因为气味物质与受体的结合时间很短。嗅觉受体神经元的感觉纤毛已经发展出一种不同寻常的解决方案。它们在静止状态下积累氯离子，并在气味检测时释放氯离子电流。氯离子电流放大受体电位，促进电兴奋。我们通过检查其分子成分的身份，亚细胞定位和调节来研究这种扩增过程。我们发现Na+/K+/2Cl（-）共转运蛋白NKCC1在纤毛膜中表达，在那里它介导氯离子积聚进入纤毛管腔。基因沉默实验表明，该转运体的活性依赖于激酶SPAK和OSR1，它们与其自身的激活激酶WNK1和WNK4一起富集在纤毛中。第二种Cl-转运体，Cl-/HCO3-交换器SLC4A1，在纤毛中表达，可能支持Cl-积累。钙依赖性氯离子通道TMEM16B （ANO2）为兴奋性氯离子电流提供了一个纤毛通道。这些发现描述了一组特定的纤毛蛋白参与阴离子基信号放大。它们提供了一种独特策略的分子概念，这种策略允许嗅觉感觉神经元作为弱感觉刺激的有效换能器运作。
The mammalian olfactory system detects an unlimited variety of odorants with a limited set of odorant receptors. To cope with the complexity of the odor world, each odorant receptor must detect many different odorants. The demand for low odor selectivity creates problems for the transduction process: the initial transduction step, the synthesis of the second messenger cAMP, operates with low efficiency, mainly because odorants bind only briefly to their receptors. Sensory cilia of olfactory receptor neurons have developed an unusual solution to this problem. They accumulate chloride ions at rest and discharge a chloride current upon odor detection. This chloride current amplifies the receptor potential and promotes electrical excitation. We have studied this amplification process by examining identity, subcellular localization, and regulation of its molecular components. We found that the Na+/K+/2Cl(-) cotransporter NKCC1 is expressed in the ciliary membrane, where it mediates chloride accumulation into the ciliary lumen. Gene silencing experiments revealed that the activity of this transporter depends on the kinases SPAK and OSR1, which are enriched in the cilia together with their own activating kinases, WNK1 and WNK4. A second Cl- transporter, the Cl-/HCO3- exchanger SLC4A1, is expressed in the cilia and may support Cl- accumulation. The calcium-dependent chloride channel TMEM16B (ANO2) provides a ciliary pathway for the excitatory chloride current. These findings describe a specific set of ciliary proteins involved in anion-based signal amplification. They provide a molecular concept for the unique strategy that allows olfactory sensory neurons to operate as efficient transducers of weak sensory stimuli.