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 receptors interact with cytoskeletal proteins, and, for NMDA receptors, such interactions regulate surface expression and channel activity. To determine whether mutant huntingtin alters NMDA receptor expression or function, we coexpressed mutant or normal huntingtin, containing 138 or 15 glutamine repeats, respectively, with NMDA receptors in a cell line and then assessed receptor channel function by patch-clamp recording and surface expression by western 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 selective for NR1/NR2B, as NR1/NR2A showed similar currents when coexpressed with mutant versus normal huntingtin. However, ion channel properties and total surface expression of the NR1 subunit were unchanged in cells cotransfected with NR1/NR2B and mutant huntingtin. Our results suggest that mutant huntingtin may increase numbers of functional NR1/NR2B-type receptors at the cell surface. Because NR1/NR2B is the predominant NMDA receptor subtype expressed in medium spiny neostriatal neurons, our findings may help explain the selective vulnerability of these neurons in HD.
Chen
N
N
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Luo
T
T
Wellington
C
C
Metzler
M
M
McCutcheon
K
K
Hayden
M R
MR
Raymond
L A
LA
D002460:Cell Line; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004553:Electric Conductivity; D006801:Humans; D000071058:Huntingtin Protein; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology; D007536:Isomerism; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013379:Substrate Specificity
C086055:HTT protein, human; D000071058:Huntingtin Protein; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate