Subtype-specific enhancement of NMDA receptor currents by mutant Huntingtin

Evidence suggests that NMDA receptor-mediated neurotoxicity plays a role in the selective neurodegeneration underlying Huntington's disease (HD), The gene mutation that causes HD encodes an expanded polyglutamine tract of >35 in huntingtin, a protein of unknown function. Both huntingtin and NMDA rec eptors interact with cytoskeletal proteins, and, for NMDA receptors, such i nteractions regulate surface expression and channel activity. To determine whether mutant huntingtin alters NMDA receptor expression or function, we c oexpressed mutant or normal huntingtin, containing 138 or 15 glutamine repe ats, respectively, with NMDA receptors in a cell line and then assessed rec eptor channel function by patch-clamp recording and surface expression by w estern blot analysis. It is interesting that receptors composed of NR1 and NR2B subunits exhibited significantly larger currents when coexpressed with mutant compared with normal huntingtin, Moreover, this effect was selectiv e for NR1/NR2B, as NR1/NR2A showed similar currents when coexpressed with m utant versus normal huntingtin. However, ion channel properties and total s urface expression of the NR1 subunit were unchanged in cells cotransfected with NR1/NR2B and mutant huntingtin, Our results suggest that mutant huntin gtin may increase numbers of functional NR1/NR2B-type receptors at the cell surface. Because NR1/NR2B is the predominant NMDA receptor subtype express ed in medium spiny neostriatal neurons, our findings may help explain the s elective vulnerability of these neurons in HD.