Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor.
Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor.
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DOI：
10.1038/cddis.2013.80
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发表时间：
2013-03-21
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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Humanin是一种分泌的生物活性肽，在多种死亡模型中具有保护作用，包括与阿尔茨海默病（AD）相关的基于细胞的神经元死亡模型。为了介导AD相关死亡模型中的保护作用，Humanin通过细胞表面受体发出信号，该受体通常由三个亚基组成：睫状神经营养因子受体α，WSX-1和gp 130（异源三聚体Humanin受体; htHNR）。然而，Humanin通过htHNR的保护作用较弱（EC 50 =1-10 μ g）;因此，可能存在该受体的另一种生理激动剂。在目前的研究中，钙调素样皮肤蛋白（CLSP），一种功能不明确的钙调素相关蛋白，被证明是分泌的，并通过htHNR抑制神经元死亡，EC 50为10-100 μ g/ml。CLSP在皮肤中高度表达，在正常人循环血液中的浓度为10.5ng/ml。当在小鼠中腹膜内施用时，重组CLSP被转运穿过血-脑脊液（CSF）屏障，并且其在CSF中的浓度在注射后1小时达到其血清浓度的1/100。这些发现表明CLSP是生理性htHNR激动剂。
Humanin is a secreted bioactive peptide that is protective in a variety of death models, including cell-based neuronal death models related to Alzheimer's disease (AD). To mediate the protective effect in AD-related death models, Humanin signals via a cell-surface receptor that is generally composed of three subunits: ciliary neurotrophic factor receptor α, WSX-1 and gp130 (heterotrimeric Humanin receptor; htHNR). However, the protective effect of Humanin via the htHNR is weak (EC50=1–10 μℳ); therefore, it is possible that another physiological agonist for this receptor exists in vivo. In the current study, calmodulin-like skin protein (CLSP), a calmodulin relative with an undefined function, was shown to be secreted and inhibit neuronal death via the htHNR with an EC50 of 10–100 pℳ. CLSP was highly expressed in the skin, and the concentration in circulating normal human blood was ∼5 nℳ. When administered intraperitoneally in mice, recombinant CLSP was transported across the blood-cerebrospinal fluid (CSF)-barrier and its concentration in the CSF reaches 1/100 of its serum concentration at 1 h after injection. These findings suggest that CLSP is a physiological htHNR agonist.
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