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

Mutations of EFHC1 gene have been identified in patients with epilepsies including juvenile myoclonic epilepsy (JME), and mice with Efhc1 deficiency exhibit epileptic phenotypes. Myoclonin1 protein encoded by EFHC1 is 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 by EFHC1 mutations, however, remain unclear. Here we report that myoclonin1 is well co–expressed with inositol 1,4,5–trisphosphate receptor type 1 (IP 3 R1) at choroid plexus and ependymal cells and these two proteins bind each other. Endoplasmic reticulum (ER) of Efhc1 –deficient mouse ( Efhc1 -/– ) cells contains larger levels of calcium ions (Ca 2+ ) than that of wild–type (WT) mice, and IP 3 –induced Ca 2+ release (IICR) from ER is higher in Efhc1 -/– 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 IP 3 R1. Myoclonin1 further binds to IP 3 R2 and IP 3 R3. Thus, our results indicate that myoclonin1 modulates ER–Ca 2+ homeostasis through interactions with IP 3 Rs and PRKCSH, and suggest that myoclonin1 dysfunctions cause impaired intracellular Ca 2+ mobilization. It’s relevance to the epileptic phenotypes of patients with EFHC1 mutations is now of interest.