Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine (polyQ) tract in huntingtin (htt) protein. Although altered calcium (Ca2+) homeostasis is suggested in HD, its molecular mechanisms have remained poorly understood despite their important role in the pathogenesis. In this study, we examined involvement of ryanodine receptor (RyR), an endoplasmic reticulum-resident Ca2+ channel, in mutant htt-induced neuronal death. Inhibitors of RyR attenuated cell death induced by mutant htt, while co-expression of RyR enhanced htt toxicity. Intracellular Ca2+ imaging revealed that mutant htt caused excessive basal Ca2+ release (Ca2+ leak) through RyR leading to depletion of internal Ca2+ store. Ca2+ leak was also observed in striatal and cortical neurons from R6/2 HD model mice. Moreover, expression of FK506-binding protein 12 (FKBP12), a RyR stabilizer, suppressed both Ca2+ leak and cell death. These results provide novel evidence suggesting altered RyR function is involved in neuronal cell death, and its stabilization might be beneficial for treatment of HD. (C) 2012 Elsevier Inc. All rights reserved.