Vasopressin: more than just an output of the circadian pacemaker? Focus on "Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei"
Vasopressin: more than just an output of the circadian pacemaker? Focus on "Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei"
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DOI：
10.1152/ajpregu.90991.2008
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发表时间：
2009-03-01
影响因子：
2.8
通讯作者：
Bittman, Eric L.
中科院分区：
文献类型：
--
作者：
Bittman, Eric L.
生理事件的时间被仔细地控制，以便不相容的过程不竞争，互补的功能一致。考虑到下丘脑在自我平衡调节中的关键作用，发现主昼夜节律起搏器位于该区域并不令人惊讶。在1972年发现视交叉上核（SCN）对于昼夜节律性是不可或缺的（18）后不久，对其解剖组织的描述加强了。神经肽的不均匀分布变得明显，小细胞加压素能神经元集中在背内侧区，含有血管活性肠多肽（VIP）的细胞集中在腹外侧区（14）。在过去的十年中，在揭示控制起搏器功能的分子机制方面取得了显著进展（综述见7）。哺乳动物昼夜节律振荡器的核心是一个复杂的反馈回路。在恒定条件下，核心时钟基因Period和Cryptochrome的转录被结合E-box基序的BMAL 1：CLOCK二聚体周期性地激活。Per和Cry的蛋白产物在几个小时的间隔后起作用以阻断这种转录激活。视黄孤儿受体调节Bmal 1表达的积极和消极的，从而参与确定的幅度，相位和周期的昼夜节律。翻译后事件，包括核心时钟基因蛋白产物的磷酸化和泛素化，也有助于调节节律性。然而，努力了解SCN的起搏器功能集中在核心转录-翻译环的操作。在恒定条件下，Per的节律性表达在背侧SCN的加压素能细胞中最为显著（5）。在VIP丰富的腹侧区域，Per表达主要由视网膜输入调节;昼夜节律相位通过CRE而不是E-box序列的激活来设定。尽管在腹外侧“核心”中时钟基因表达的自由运行节律不明显，但VIP或VPAC 2受体的消除严重损害SCN中电活动的运动节律性和昼夜节律（1，13）。这引起了人们对VIP作为维持固有节律起搏神经元的相位相干性的关键SCN内信号的关注。背侧SCN中的加压素能细胞获得的荣誉较少：它们被认为是起搏器关键核心的下游，而不是细胞振荡连贯性的组成部分。
THE TIMING OF PHYSIOLOGICAL EVENTS is carefully controlled so that incompatible processes do not compete and complementary functions coincide. Given the pivotal role of the hypothalamus in homeostatic regulation, the discovery that a master circadian pacemaker resides in this region was not surprising. Soon after the discovery in 1972 that the suprachiasmatic nucleus (SCN) is indispensable for circadian rhythmicity (18), description of its anatomical organization intensified. A heterogeneous distribution of neuropeptides became apparent, with parvicellular vasopressinergic neurons concentrated in the dorsomedial region and cells containing vasoactive intestinal polypeptide (VIP) in the ventrolateral portion (14).Over the past decade, remarkable progress has been made in uncovering the molecular mechanisms that govern pacemaker function (see 7 for review). At the core of the mammalian circadian oscillator lies an intricate arrangement of feedback loops. In constant conditions, the transcription of the core clock genes Period and Cryptochrome is periodically activated by BMAL1: CLOCK dimers that bind E-box motifs. The protein products of Per and Cry act after an interval of several hours to block this transcriptional activation. Retinoic orphan receptors regulate Bmal1 expression both positively and negatively, and thus participate in determination of the amplitude, phase and period of circadian rhythms. Post-translational events, including phosphorylation and ubiquitylation of the protein products of the core clock genes, also contribute to regulation of rhythmicity. Nevertheless, efforts to understand pacemaker function of the SCN have focused on operation of the core transcriptional-translational loop. Rhythmic Per expression in constant conditions is most prominent in the vasopressinergic cells of the dorsal SCN (5). In the VIP-rich ventral region, Per expression is regulated primarily by retinal input; circadian phase is set through activation at CRE rather than E-box sequences. Although free running rhythms of clock gene expression are not evident in the ventrolateral “core,” elimination of either VIP or the VPAC2 receptor severely compromises locomotor rhythmicity and circadian rhythms of electrical activity in the SCN (1, 13). This has drawn attention to VIP as a critical intra-SCN signal that maintains phase coherence of intrinsically rhythmic pacemaker neurons. Vasopressinergic cells in the dorsal SCN have received less of the glory: they have been regarded as downstream from the critical core of the pacemaker, rather than integral to coherence of cellular oscillations.