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NMDA receptors are ionotropic glutamate receptors that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system. Recombinant GluN1-1a/GluN2D receptors are characterized by low channel open probability and prolonged deactivation time course following the removal of agonist. Here, we show that the deactivation time course, agonist potency, and single channel properties of GluN2D-containing NMDA receptors are modulated by alternative RNA splicing of GluN1. Our results demonstrate that GluN1 exon 5, which encodes a 21-amino-acid insert in the amino-terminal domain, is a key determinant of GluN1/GluN2D receptor function. GluN1-1b/GluN2D receptors, which contain the residues encoded by exon 5, deactivate with a dual exponential time course described by a τFAST of 410 ms and a τSLOW of 1100 ms. This time course is 3-fold more rapid than that for exon 5-lacking GluN1-1a/GluN2D, which deactivates with a τFAST of 1100 ms and a τSLOW of 3400 ms. Exon 5-containing NMDA receptors also have a two-fold higher open probability (0.037) than exon 5-lacking receptors (0.017). Furthermore, inclusion of exon 5-encoded residues within the GluN1-1b subunit decreases the potency for the endogenous agonist l-glutamate. Evaluation of receptor kinetics for NMDA receptors containing mutated GluN1-1b subunits and wild-type GluN2D identified residue Lys211 in GluN1-1b as a key determinant of exon 5 control of the deactivation time course and glutamate potency. Evaluation of a kinetic model of GluN1/GluN2D gating suggests that residues encoded by exon 5 influence several rate-limiting steps. These data demonstrate that the GluN1 subunit is a key determinant of the kinetic and pharmacological properties of GluN2D-containing NMDA receptors.
Pubmed ID: 22641781
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These programs have been written over the last 20 years for analysis of our own results. They all do some things that are still not available in any commercial program. The programs are written in protected-mode 32-bit Fortran 90, with some assembler subroutines for fast graphics, and the Gino graphics library. Thus they are essentially DOS programs, though they are usually run from Windows, either via a desktop icon (the .ico files) or in the DOS box. The manuals (now in pdf format), have now all been collected into a single document, DCMANUALS.PDF, which should be downloaded, and the bits that you need can then be printed. Note that some sections are common to many or all programs, e.g. the notes on the graph and histogram drawing subroutines, and it is important to read this before using any of the programs (though there is a lot of online help (hit F1) for the graphics, and also in SCAN. Sponsor. Our work was supported by the Wellcome Trust (project grant 074491) and the Medical Research Council (programme grant G0400869).
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