Lilliehook Christina, Bozdagi Ozlem, Yao Jun, Gomez-Ramirez Manuel, Zaidi Nikhat F, Wasco Wilma, Gandy Sam, Santucci Anthony C, Haroutunian Vahram, Huntley George W, Buxbaum Joseph D
Laboratory of Molecular Neuropsychiatry and Department of Psychiatry, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA.
J Neurosci. 2003 Oct 8;23(27):9097-106. doi: 10.1523/JNEUROSCI.23-27-09097.2003.
Calsenilin has been identified as a presenilin-binding protein, a transcription factor regulating dynorphin expression, and a beta-subunit of Kv4 channels and could, thus, be a multifunctional protein. To study these functions of calsenilin in vivo and to determine the neuroanatomical expression pattern of calsenilin, we generated mice with a disruption of the calsenilin gene by the targeted insertion of the beta-galactosidase gene. We found that calsenilin expression (as represented by beta-galactosidase activity) is very restricted but overlaps better with that of presenilins and Kv4 channels than with dynorphin, suggesting that calsenilin may regulate presenilin and Kv4 channels in brain. Abeta peptide levels are reduced in calsenilin knock-out mice, demonstrating that calsenilin affects presenilin-dependent gamma-cleavage in vivo. Furthermore, long-term potentiation (LTP) in dentate gyrus of hippocampus, in which calsenilin is strongly and selectively expressed, is enhanced in calsenilin knock-out mice. This enhancement of LTP coincides with a downregulation of the Kv4 channel-dependent A-type current and can be mimicked in wild-type animals by a Kv4 channel blocker. The data presented here show that lack of calsenilin affects both Abeta formation and the A-type current. We suggest that these effects are separate events, caused by a common mechanism possibly involving protein transport.
钙调素已被鉴定为一种早老素结合蛋白、一种调节强啡肽表达的转录因子以及Kv4通道的β亚基，因此可能是一种多功能蛋白。为了在体内研究钙调素的这些功能并确定其神经解剖学表达模式，我们通过靶向插入β-半乳糖苷酶基因，培育出了钙调素基因缺失的小鼠。我们发现，钙调素的表达（以β-半乳糖苷酶活性表示）非常局限，但与早老素和Kv4通道的表达重叠程度高于与强啡肽的重叠程度，这表明钙调素可能在大脑中调节早老素和Kv4通道。在钙调素基因敲除小鼠中，β淀粉样肽水平降低，这表明钙调素在体内影响早老素依赖的γ切割。此外，在海马齿状回中强烈且选择性表达钙调素的长期增强效应（LTP）在钙调素基因敲除小鼠中增强。LTP的这种增强与Kv4通道依赖性A型电流的下调一致，并且可以在野生型动物中通过Kv4通道阻滞剂模拟。此处呈现的数据表明，缺乏钙调素会影响β淀粉样蛋白的形成和A型电流。我们认为这些效应是由一个可能涉及蛋白质转运的共同机制引起的独立事件。
