Epilepsy protein myoclonin1 interacts with inositol 1,4,5–trisphosphate (IP3) receptor and reduces Ca2+store in endoplasmic reticulum

Abstract

AbstractMutations ofEFHC1gene have been identified in patients with epilepsies including juvenile myoclonic epilepsy (JME), and mice withEfhc1deficiency exhibit epileptic phenotypes. Myoclonin1 protein encoded byEFHC1is not expressed in neurons but in cells with motile cilia including those of choroid plexus and ependymal cells which form an epithelial layer lining brain ventricles. Detailed molecular basis of epilepsies caused byEFHC1mutations, however, remain unclear. Here we report that myoclonin1 is well co–expressed with inositol 1,4,5–trisphosphate receptor type 1 (IP3R1) at choroid plexus and ependymal cells and these two proteins bind each other. Endoplasmic reticulum (ER) ofEfhc1–deficient mouse (Efhc1-/–) cells contains larger levels of calcium ions (Ca2+) than that of wild–type (WT) mice, and IP3–induced Ca2+release (IICR) from ER is higher inEfhc1-/–cells than that of WT. Furthermore, myoclonin1 revealed to interact with PRKCSH, also known as a protein kinase C substrate 80K–H which interacts with IP3R1. Myoclonin1 further binds to IP3R2 and IP3R3. Thus, our results indicate that myoclonin1 modulates ER–Ca2+homeostasis through interactions with IP3Rs and PRKCSH, and suggest that myoclonin1 dysfunctions cause impaired intracellular Ca2+mobilization. It’s relevance to the epileptic phenotypes of patients withEFHC1mutations is now of interest.