Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington’s disease

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder that has no cure. HD primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Htt^exp and MSN neurodegeneration remains elusive. My laboratory discovered that mutant Htt^exp protein specifically binds to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (InsP<inf>3</inf>R1), an intracellular Ca²⁺ release channel. Moreover, we found that Htt^exp association with InsP<inf>3</inf>R1 causes sensitization of InsP<inf>3</inf>R1 to activation by InsP<inf>3</inf> in planar lipid bilayers and in primary MSN. Mutant Htt^exp has also been shown to activate Ca²⁺-permeable NR2B-containing NMDA receptors. All these results suggested that deranged neuronal Ca²⁺ signaling may play an important role in pathogenesis of HD. In support of this idea, we demonstrated a connection between abnormal Ca²⁺ signaling and apoptosis of MSN cultured from YAC128 HD mouse model. These results indicate that InsP<inf>3</inf>R and other Ca²⁺ signaling proteins should be considered as potential therapeutic targets for treatment of HD.