van den Pol A N, Gao X B, Obrietan K, Kilduff T S, Belousov A B
Department of Neurosurgery, Yale University Medical School, New Haven, Connecticut 06520, USA.
J Neurosci. 1998 Oct 1;18(19):7962-71. doi: 10.1523/JNEUROSCI.18-19-07962.1998.
A new orexigenic peptide called hypocretin (orexin) has recently been described in neurons of the lateral hypothalamus and perifornical area. The medial and lateral hypothalamus have been loosely called satiety and feeding centers of the brain, respectively. Approximately one-third of all medial and lateral hypothalamic neurons tested, but not hippocampal neurons, show a striking nanomolar sensitivity to hypocretin. As studied with calcium digital imaging with fura-2, hypocretin raises cytoplasmic calcium via a mechanism based on G-protein enhancement of calcium influx through plasma membrane channels. The peptide has a potent effect at both presynaptic and postsynaptic receptors. Most synaptic activity in hypothalamic circuits is attributable to axonal release of GABA or glutamate. With whole-cell patch-clamp recording, we show that hypocretin, acting directly at axon terminals, can increase the release of each of these amino acid transmitters. Two hypocretin peptides, hypocretin-1 and hypocretin-2, are coded by a single gene; neurons that respond to one peptide also respond to the other. In addition to its effect on feeding, we find that this peptide also regulates the synaptic activity of physiologically identified neuroendocrine neurons studied in hypothalamic slices containing the arcuate nucleus, suggesting a second function of hypocretin in hormone regulation. The widespread distribution of hypocretin axons, coupled with the strong response to the peptide at both presynaptic and postsynaptic sites, suggests that the peptide probably modulates a variety of hypothalamic regulatory systems and could regulate the axonal input to these regions presynaptically.
最近，在外侧下丘脑和穹窿周区的神经元中发现了一种名为下丘脑泌素（食欲素）的新型促食欲肽。内侧和外侧下丘脑分别被大致称为大脑的饱腹感中枢和进食中枢。在所有接受测试的内侧和外侧下丘脑神经元中，约三分之一的神经元对下丘脑泌素表现出显著的纳摩尔敏感性，而海马神经元则没有。通过使用fura-2进行钙数字成像研究发现，下丘脑泌素通过一种基于G蛋白增强钙通过质膜通道内流的机制来提高细胞质钙水平。该肽在突触前和突触后受体上均有强效作用。下丘脑回路中的大多数突触活动归因于GABA或谷氨酸的轴突释放。通过全细胞膜片钳记录，我们发现下丘脑泌素直接作用于轴突终末，可增加这两种氨基酸递质的释放。两种下丘脑泌素肽，即下丘脑泌素-1和下丘脑泌素-2，由单个基因编码；对一种肽有反应的神经元对另一种肽也有反应。除了对进食的影响外，我们还发现这种肽还调节含有弓状核的下丘脑切片中经生理学鉴定的神经内分泌神经元的突触活动，这表明下丘脑泌素在激素调节中具有第二种功能。下丘脑泌素轴突的广泛分布，加上在突触前和突触后位点对该肽的强烈反应，表明该肽可能调节多种下丘脑调节系统，并可能在突触前调节向这些区域的轴突输入。
