Molecular Determinants Controlling Functional Properties of AMPARs and NMDARs in the Mammalian CNS
L-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) are the two major types of postsynaptic glutamate receptors (GluRs) that mediate excitatory synaptic transmission in the mammalian central ne
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Molecular Determinants Controlling Functional Properties of AMPARs and NMDARs in the Mammalian CNS H. MONYER, P. JONAS, and J. ROSSlER
Abbreviations AMPARs Baz+ C-terminal Ca1l3 Caz+ CNS EPSC GABAR GluR H HEK cells I-V curve IC so
Kd LTD LTP M2 Mgz+ mRNA N-terminal N NMDARs Q R RT-PCR
a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors Barium Carboxy-terminal Ca1l3 fields of the hippocampus Calcium Central nervous system Excitatory postsynaptic current y-Amino-butyric-acid receptor Glutamate receptors Histidine Human embryonic kidney cells Current-voltage relation Half-maximal inhibitory concentration Dissociation constant Long-term depression Long-term potentiation Membrane segment 2 Magnesium Messenger ribonucleic acid Amino-terminal Asparagine N-methyl-n-aspartate receptors Glutamine Arginine Reverse transcriptase-polymerase chain reaction
A. Introduction L-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) and N-methyl-n-aspartate receptors (NMDARs) are the two major types of postsynaptic glutamate receptors (GluRs) that mediate excitatory synaptic transmission in the mammalian central nervous system (CNS). Both AMPARs P. Jonas et al. (eds.), Ionotropic Glutamate Receptors in the CNS © Springer-Verlag Berlin Heidelberg 1999
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and NMDARs are multimeric proteins, probably tetramers, formed by a variety of molecularly distinct subunits. AMPARs can be assembled from four types of subunits, termed GluR-A, -B, -C, and -D (or, in an alternative nomenclature, GluR1, GluR2, GluR3, and GluR4). Additional molecular diversity of AMPARs is generated by alternative splicing of the flip-flop module and RNA editing at the Q/R and RIG site. NMDARs are heteromers primarily assembled from NR1 subunits and NR2A, B, C, or D subunits. Various splice variants have been identified for the NR1 subunit, and a new NR3 subunit has been discovered recently. Considering all combinatorial possibilities, the molecular diversity of glutamate-receptor channels is considerable (HOLLMANN, this volume). What is the functional significance of the molecular diversity of GluRs? In this chapter, we review the relation between structure and function for both recombinant and native GluRs. We suggest that GluR-subunit expression, alternative splicing, and RNA editing contribute to differential signalling at glutamatergic synapses in the mammalian CNS.
B. AMPA Receptors I. Recombinant Receptors Members of the AMPAR subunit family (GluR-A, -B, -C, and -D) have been recombinantly expressed in both mammalian cell lines, e.g. human embryonic kidney (HEK) cells, and Xenopus oocytes (HOLLMANN et al. 1989; NAKANISHI et al. 1990; VERDOORN et al. 1991; BURNASHEV et al. 1992a). Unlike many other ligand-gated ion channels, such as nicotinic acetylcholine receptors of skeletal muscle, glycine receptors, or y.amino-butyric-acid-A receptors (GABAARs), heterologously expressed AMPAR subunits can form both homomeric and heteromeric receptors. 1. Divalent Permeability
Homomeric AMPARs assembled from different subunits d
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