Figure 4.

The model of Ca²⁺ dysregulation in HD. In HD MSN, the Htt^exp perturbs Ca²⁺ signaling through several synergistic mechanisms. Htt^exp enhances function of NR2B-containing NMDAR, probably by promoting trafficking to the plasma membrane. Htt^exp binds strongly to the InsP₃R1C terminus and sensitizes the InsP₃R1 to activation by InsP₃. The low levels of glutamate released from corticostriatal projection neurons lead to supranormal Ca²⁺ influx by NMDAR and Ca²⁺ release through the InsP₃R1. Additional Ca²⁺ influx to MSN is mediated by voltage-gated Ca²⁺ channels (VGCCs). Dopamine released from midbrain dopaminergic neurons stimulates D1-class and D2-class DARs, which are expressed abundantly in MSNs. D1-class DARs are coupled to activation of adenyl cyclase, increase in cAMP levels and activation of PKA. PKA potentiates glutamate-induced Ca²⁺ signals by facilitating the activity of NMDAR and InsP₃R1. D2 receptors are coupled directly to InsP₃ production and activation of InsP₃R1. Supranormal Ca²⁺ signals activate calpain, which cleave Htt^exp and other substrates. Excessive cytosolic Ca²⁺ signals result in mitochondrial Ca²⁺ uptake by MCU, which eventually triggers mtPTP opening and apoptosis. The mitochondrial Ca²⁺ handling is further destabilized by direct association of Htt^exp with mitochondria. Antidopamine agent tetrabenazine (TBZ) is approved by the US FDA for symptomatic treatment of HD. NMDAR antagonist memantine (MMT), putative ‘mitochondrial agent’ Dimebon and ‘mitochondrial stabilizers’ creatine and CoQ10 are tested in HD clinical trials. Antiglutamate agent riluzole was tested and failed [66]. Adapted from [77].