THE 5'-UNTRANSLATED REGION OF THE N-METHYL-D-ASPARTATE RECEPTOR NR2A SUBUNIT CONTROLS EFFICIENCY OF TRANSLATION

The N-methyl-D-aspartate (NMDA) receptor plays a central role in such phenomena as long term potentiation and excitotoxicity. This importanc e in defining both function and viability suggests that neurons must c arefully control their expression of NMDA receptors, Whereas the NR1 s ubunit of the NMDA receptor is ubiquitously transcribed throughout the brain, transcription of NR2 subunits is spatially and temporally cont rolled, Since heteromeric assembly of both subunits is required for ef ficient functional expression, post-transcriptional modification of ei ther subunit would affect NMDA receptor activity. Here it is demonstra ted that the 5'-untranslated region (5'-UTR) of the NR2A subunit sever ely restricts its protein translation in both Xenopus oocytes and in a n in vitro translation system. Mutational analysis of the 5'-UTR impli cates secondary structure as the major translational impediment, while the five alternate start codons play minor roles, An important biolog ical role for the 5'-UTR of NR2A is further suggested by the unusually high level of sequence conservation between species. In contrast, the 5'-UTR of NR1 does not inhibit translation and is not conserved. Take n together, these findings suggest a mechanism for modulation of NMDA receptor activity through the control of translational efficiency of a single subunit.