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J Biol Chem, Vol. 274, Issue 1, 151-157, January 1, 1999
From the Laboratory of Neurochemistry, NIDCD, National Institutes
of Health, Bethesda, Maryland 20892
The number, composition, and location of
receptors in neurons are critically important factors in determining
the neuron's response to neurotransmitters. The functional expression
of receptors appears to be regulated both generally, at the level of
transcription or translation, and locally, at the level of the
individual synapse. A key component in the regulation of any protein is
its turnover rate, which, measured in half-lives, ranges from a few
minutes to several days. In the present study, we measured the turnover rates of subunits of N-methyl-D-aspartate
(NMDA) and 
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA) receptors, the two major ionotropic glutamate receptors, using
cultured cerebellar granule cells. Turnover rates for NR1, NR2A/B,
GluR2/3, and GluR4 subunits were determined by pulse-chase labeling of
cells with [35S]methionine. Half-lives were found to be
18 ± 5 h and 23 ± 8 h for the AMPA receptor
subunits GluR2/3 and GluR4, respectively, and 16 ± 5 h for
NR2A. The NR1 subunit showed a biphasic decay with half-lives of 2 and
34 h for the rapidly and slowly degraded populations,
respectively. Splice variants of the NR1 subunit with different
carboxyl-terminal cassettes, C2 and C2', showed similar biphasic
degradation patterns. To further characterize the rapidly degraded pool
of NR1, surface receptors were labeled by biotinylation, and half-lives
of the biotinylated proteins were determined. All surface NR1 was
slowly degraded with a pattern similar to that of NR2A, GluR2/3, and
GluR4, suggesting that the rapidly degraded pool is confined to the
cytoplasm and not assembled with NR2 subunits. A significant amount of
NR1 was not immunoprecipitated by NR2 subunit-specific antibodies after
solubilization with deoxycholate. This unassembled pool, but not the
assembled one, was greatly diminished following treatment of
cycloheximide for 5 h, indicating that the rapidly degraded pool
of NR1 is not assembled with NR2. These results show that NMDA and AMPA
receptors have similar turnover rates, but NMDA receptors have a
separate pool of NR1 subunits that is rapidly degraded and accounts for
most of the intracellular pool.
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