THE TYPE-1 INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR GENE IS ALTERED IN THE OPISTHOTONOS MOUSE

The opisthotonos (opt) mutation arose spontaneously in a C57BL/Ks-db(2 J) colony and is the only known, naturally occurring allele of opt. Th is mutant mouse was first identified based on its ataxic and convulsiv e phenotype. Genetic and molecular data presented here demonstrate tha t the type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1) protein, which serves as an IP3-gated channel to release calcium from intracell ular stores, is altered in the opt mutant, A genomic deletion in the I P(3)R1 gene removes two exons from the IP(3)R1 mRNA but does not inter rupt the translational reading frame, The altered protein is predicted to have lost several modulatory sites and is present at markedly redu ced levels in opt homozygotes. Nonetheless, a strong calcium release f rom intracellular stores can be elicited in cerebellar Purkinje neuron s treated with the metabotropic glutamate receptor (mGluR) agonist qui squalate (QA). QA activates Group I mGluRs linked to GTP-binding prote ins that stimulate phospholipase C and subsequent production of the in tracellular messenger IP3, leading to calcium mobilization via the IP( 3)R1 protein. The calcium response in opt homozygotes shows less atten uation to repeated QA application than in control littermates. These d ata suggest that the convulsions and ataxia observed in opt mice may b e caused by the physiological dysregulation of a functional IP(3)R1 pr otein.