The Type 1 Inositol 1,4,5-Trisphosphate Receptor Gene Is Altered in theopisthotonosMouse

Abstract

The opisthotonos (opt) mutation arose spontaneously in a C57BL/Ks-db2J colony and is the only known, naturally occurring allele of opt. This mutant mouse was first identified based on its ataxic and convulsive phenotype. Genetic and molecular data presented here demonstrate that the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) protein, which serves as an IP3-gated channel to release calcium from intracellular stores, is altered in the opt mutant. A genomic deletion in the IP3R1 gene removes two exons from the IP3R1 mRNA but does not interrupt the translational reading frame. The altered protein is predicted to have lost several modulatory sites and is present at markedly reduced levels in opt homozygotes. Nonetheless, a strong calcium release from intracellular stores can be elicited in cerebellar Purkinje neurons treated with the metabotropic glutamate receptor (mGluR) agonist quisqualate (QA). QA activates Group 1 mGluRs linked to GTP-binding proteins that stimulate phospholipase C and subsequent production of the intracellular messenger IP3, leading to calcium mobilization via the IP3R1 protein. The calcium response in opt homozygotes shows less attenuation to repeated QA application than in control littermates. These data suggest that the convulsions and ataxia observed in opt mice may be caused by the physiological dysregulation of a functional IP3R1 protein.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…These mutant mice display some features of an ataxic and convulsive phenotype. Genetic data showed that the IP3R1 gene is modified in the opt mice [52]. A partial deletion of IP3R1 removes two exons but does not interrupt the translational reading frame.…”

An antidepressant behaviour in mice carrying a gene-specific InsP3R1, InsP3R2 and InsP3R3 protein knockdown

“…Several skeletal-muscle pathologies such as malignant hyperthermia, porcine stress syndrome, central-core disease, can be caused by mutations in ryanodine receptors (Missiaen et al, 2000). Brain InsP3Rs have been hypothesized to contribute to the pathology of episthotonos in mice (Street et al, 1997). Disturbance in InsP3R and RyR appears to be involved in neurodegenerative diseases such as Alzheimer's disease (Mattson and Chan, 2003).…”

Combined Neuro-Cardiogenic Epilepsy Syndromes and Novel Mechanistic Insights

“…In addition, inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) intracellular Ca 2+ release channels, which localize to intracellular ER Ca 2+ stores, have been associated with seizures in mice (Street et al, 1997). However, a mechanistic relationship between dysfunction of intracellular Ca 2+ release channels and seizures has not been established.…”

“…However, a mechanistic relationship between dysfunction of intracellular Ca 2+ release channels and seizures has not been established. Ca 2+ is an important neuronal signaling molecule and intracellular Ca 2+ release channels are an important source including IP3R1-3 isoforms (Mignery et al, 1989;Street et al, 1997) and the related ryanodine receptor isoforms (RyR1-3) (Henzi & MacDermott, 1992;Kostyuk & Verkhratsky, 1994). Interestingly, mutation carriers with RyR2 mutations have been shown to exhibit syncope, seizures and cardiac arrhythmias (Postma et al, 2005).…”