Cholecystokinin-A receptors regulate photic input pathways to the circadian clock
Cholecystokinin-A receptors regulate photic input pathways to the circadian clock
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DOI：
10.1096/fj.07-9372com
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发表时间：
2008-05-01
期刊：
影响因子：
4.8
通讯作者：
Ikeda, Masayuki
中科院分区：
文献类型：
--
作者：
Shimazoe, Takao;Morita, Mitsutaka;Ikeda, Masayuki
日常行为很大程度上受到内部产生的昼夜节律的支配，但潜在的机制仍不清楚。在哺乳动物中，光诱导行为的明暗循环涉及从本质上感光的视网膜神经节细胞和经典光感受器通路到视交叉上核（SCN）的信号传导。然而，经典的光感受器通路如何与光敏神经节细胞一起工作尚不完全清楚。尽管胆囊收缩素（CCK）肽已被证明存在于多种脊椎动物的视网膜中，但其在系统水平上的功能尚不清楚。在本研究中，我们使用 CCK-A 受体敲除小鼠研究了 CCK-A 受体在光诱导中的可能作用。基因敲除盒内的 lacZ 报告基因揭示了 CCK-A 受体在生物钟系统中的精确定位。我们证明CCK-A受体主要位于甘氨酸能无长突细胞上，但很少在SCN神经元上发现。此外，Ca2+ 成像分析表明，CCK-A 激动剂 CCK-8 硫酸盐 (CCK-8s) 可动员无长突细胞中的细胞内 Ca2+，但不能动员谷氨酸受体 SCN 神经元。此外，在 CCK-A 受体敲除小鼠中，光脉冲诱导的 SCN 中 mPer1/mPer2 基因表达、行为相移和瞳孔反射显着降低。这些数据表明CCK-A受体在非成像感光中的新功能可能是通过无长突细胞介导的信号转导途径实现的。
Daily behaviors are strongly dominated by internally generated circadian rhythms, but the underlying mechanisms remain unclear. In mammals, photoentrainment of behaviors to light-dark cycles involves signaling from both intrinsically photosensitive retinal ganglion cells and classic photoreceptor pathways to the suprachiasmatic nucleus (SCN). How classic photoreceptor pathways work with the photosensitive ganglion cells, however, is not fully understood. Although cholecystokinin (CCK) peptide has been shown to be present in a variety of vertebrate retinas, its function at a systems level is also unknown. In the present study we examined a possible role of CCK-A receptors in photoentrainment using CCK-A receptor knockout mice. The lacZ reporter gene within a gene-knockout cassette revealed precise localization of CCK-A receptors in the circadian clock system. We demonstrated that CCK-A receptors were located predominately on glycinergic amacrine cells but were rarely found on SCN neurons. Moreover, Ca2+ imaging analysis demonstrated that the CCK-A agonist, CCK-8 sulfate (CCK-8s), mobilized intracellular Ca2+ in amacrine cells but not glutamate-receptive SCN neurons. Furthermore, light pulse-induced mPer1/mPer2 gene expression in SCN, behavioral phase shifts, and the pupillary reflex were significantly reduced in CCK-A receptor knockout mice. These data indicate a novel function of CCK-A receptors in the nonimage-forming photoreception presumably via amacrine cell-mediated signal transduction pathways.