Genazzani A A, Carafoli E, Guerini D
Department of Biochemistry III, Swiss Federal Institute of Technology, 8092 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5797-801. doi: 10.1073/pnas.96.10.5797.
In the central nervous system, release of Ca2+ from intracellular stores contributes to numerous functions, including neurotransmitter release and long-term potentiation and depression. We have investigated the developmental profile and the regulation of inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) in primary cultures of cerebellar granule cells. The expression of both receptor types increases during development. Whereas the expression of type 1 IP3R appears to be regulated by Ca2+ influx through L type channels or N-methyl-D-aspartate (NMDA) receptors, RyR levels increase independently of Ca2+. The main target of Ca2+-influx-regulating IP3R expression is the Ca2+ calmodulin-dependent protein phosphatase calcineurin, because pharmacological blockade of this protein abolishes IP3R expression. Although calcineurin has been shown to regulate the phosphorylation state of the IP3R, the effect described here is at the transcriptional level because IP3R mRNA changes in parallel with protein levels. Thus, calcineurin plays a dual role in IP3R-mediated Ca2+ signaling: it regulates IP3R function by dephosphorylation in the short-term time scale and IP3R expression over more extended periods.
在中枢神经系统中，细胞内钙库释放Ca2+参与多种功能，包括神经递质释放以及长时程增强和抑制。我们研究了小脑颗粒细胞原代培养物中肌醇1,4,5-三磷酸受体（IP3R）和兰尼碱受体（RyR）的发育情况及其调控。两种受体类型的表达在发育过程中均增加。1型IP3R的表达似乎受通过L型通道或N-甲基-D-天冬氨酸（NMDA）受体的Ca2+内流调控，而RyR水平的增加与Ca2+无关。调节IP3R表达的Ca2+内流的主要靶点是Ca2+钙调蛋白依赖性蛋白磷酸酶钙调神经磷酸酶，因为对该蛋白的药理学阻断会消除IP3R的表达。尽管已证明钙调神经磷酸酶可调节IP3R的磷酸化状态，但此处描述的作用是在转录水平，因为IP3R mRNA与蛋白水平平行变化。因此，钙调神经磷酸酶在IP3R介导的Ca2+信号传导中起双重作用：它在短时间尺度上通过去磷酸化调节IP3R功能，并在更长时间段内调节IP3R表达。
