Department of Pharmacology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
Cell Death Dis. 2013 Mar 21;4(3):e555. doi: 10.1038/cddis.2013.80.
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.
人源神经保护因子是一种分泌型生物活性肽，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。为了在与 AD 相关的死亡模型中发挥保护作用，人源神经保护因子通过细胞表面受体发挥作用，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 gp130（三聚体人源神经保护因子受体；htHNR）。然而，人源神经保护因子通过 htHNR 发挥的保护作用较弱（EC50=1-10 μM）；因此，体内可能存在该受体的另一种生理性激动剂。在本研究中，钙调蛋白样皮肤蛋白（CLSP）是一种功能尚未明确的钙调蛋白相关蛋白，被证明可通过 htHNR 分泌并抑制神经元死亡，其 EC50 为 10-100 pM。CLSP 在皮肤中高表达，在循环正常人体血液中的浓度约为 5 nM。当以重组形式经腹腔注射入小鼠时，CLSP 可穿过血脑屏障，并且在注射后 1 小时，其在脑脊液中的浓度达到血清浓度的 1/100。这些发现表明 CLSP 是一种生理性 htHNR 激动剂。
