Calcium-Activated Calpain Specifically Cleaves Glutamate Receptor IIA But Not IIB at the Drosophila Neuromuscular Junction

作者：Elsayed Metwally, Guoli Zhao, Wenhua Li, Qifu Wang, Yongqing Zhang · 发表于：Journal of Neuroscience · 年份：2019 · DOI：10.1523/jneurosci.2213-17.2019 · 被引用次数：17 · 研究领域：Calpain Protease Function and Regulation、Neuroscience and Neuropharmacology Research、Neurobiology and Insect Physiology Research

Calpains are calcium-dependent, cytosolic proteinases active at neutral pH. They do not degrade but cleave substrates at limited sites. Calpains are implicated in various pathologies, such as ischemia, injuries, muscular dystrophy, and neurodegeneration. Despite so, the physiological function of calpains remains to be clearly defined. Using the neuromuscular junction of Drosophila of both sexes as a model, we performed RNAi screening and uncovered that calpains negatively regulated protein levels of the glutamate receptor GluRIIA but not GluRIIB. We then showed that calpains enrich at the postsynaptic area, and the calcium-dependent activation of calpains induced cleavage of GluRIIA at Q788 of its C terminus. Further genetic and biochemical experiments revealed that different calpains genetically and physically interact to form a protein complex. The protein complex was required for the proteinase activation to downregulate GluRIIA. Our data provide a novel insight into the mechanisms by which different calpains act together as a complex to specifically control GluRIIA levels and consequently synaptic function. SIGNIFICANCE STATEMENT Calpain has been implicated in neural insults and neurodegeneration. However, the physiological function of calpains in the nervous system remains to be defined. Here, we show that calpain enriches at the postsynaptic area and negatively and specifically regulates GluRIIA, but not IIB, level during development. Calcium-dependent activation of cal...