Article

Structure and assembly mechanism for heteromeric kainate receptors.

Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, DHHS, Bethesda, MD 20892, USA.
Neuron (Impact Factor: 15.98). 07/2011; 71(2):319-31. DOI: 10.1016/j.neuron.2011.05.038
Source: PubMed

ABSTRACT Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5-7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of K(d) 11 nM, 32,000-fold lower than the K(d) for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors.

1 Follower
 · 
110 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acid-sensing ion channels (ASICs) are widely expressed protongated Na+ channels playing a role in tissue acidosis and pain. A trimeric composition of ASICs has been suggested by crystallization. Upon coexpression of ASIC1a and ASIC2a in Xenopus oocytes, we observed the formation of heteromers and their coexistence with homomers by electrophysiology, but could not determine whether heteromeric complexes have a fixed subunit stoichiometry or whether certain stoichiometries are preferred over others. We therefore imaged ASICs labeled with green and red fluorescent proteins on a single-molecule level, counted bleaching steps from GFP and colocalized them with red tandem tetrameric mCherry for many individual complexes. Combinatorial analysis suggests a model of random mixing of ASIC1a and ASIC2a subunits to yield both 2:1 and 1:2 ASIC1a: ASIC2a heteromers together with ASIC1a and ASIC2a homomers.
    Proceedings of the National Academy of Sciences 06/2014; 111(22):8281-6. DOI:10.1073/pnas.1324060111 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Here we present the synthesis, pharmacological activity, and molecular docking of novel non-competitive antagonists of GluK2 receptor. The compounds concerned are derivatives of indole and carbazole and are the second reported series of non-competitive antagonists of the GluK2 receptor (the first one was also published by our group). The activity of the indole derivatives is in the micromolar range, as in the case of the first series of non-competitive GluK2 receptor antagonists. We have found that designed carbazole derivatives are devoid of activity. Active indole derivatives interact with the transduction domain of the GluK2 receptor, i.e., the domain which links the transmembrane region of the receptor with the agonist-binding domain. The binding pocket is situated within one receptor subunit.
    Medicinal Chemistry Research 02/2014; 24(2):810-817. DOI:10.1007/s00044-014-1171-1 · 1.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ionotropic glutamate receptors (iGluRs) mediate the vast majority of excitatory neurotransmission in the central nervous system of vertebrates. In the protein family of iGluRs, kainate receptors (KARs) comprise the probably least well understood receptor class. Although KARs act as key players in the regulation of synaptic network activity, many properties and functions of these proteins remain elusive until now. Especially the precise pre-, extra-, and postsynaptic localization of KARs plays a critical role for neuronal function, as an unbalanced localization of KARs would ultimately lead to dysregulated neuronal excitability. Recently, important advances in the understanding of the regulation of surface expression, function, and agonist-dependent endocytosis of KARs have been achieved. Post-translational modifications like PKC-mediated phosphorylation and SUMOylation have been reported to critically influence surface expression and endocytosis, while newly discovered auxiliary proteins were shown to shape the functional properties of KARs.
    09/2014; 4(3):565-595. DOI:10.3390/membranes4030565

Full-text (2 Sources)

Download
59 Downloads
Available from
Jun 2, 2014