Kainate Receptors: Novel Signaling Insights

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4.1 Glutamate receptors

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    Search results 1 to out of for Dlg4. RGD Dlg4. MGI Dlg4. UniProt Feature. GXD Expression. Click here! The association of kainate receptor ATD dimers is generally weaker than the association of AMPA receptor ATD dimers, but both show a general pattern of increased heterodimer stability as compared to the homodimers of their constituents, matching well physiologically observed receptor combinations.

    The free energy maps of AMPA and kainate receptor ATD dimers provide a framework for the interpretation of observed receptor subtype combinations and possible assembly pathways. At excitatory synapses in the brain of vertebrates, signal transduction is mediated by a large family of glutamate receptor ion channels iGluRs encoded by 18 iGluR subunit genes.

    These membrane proteins assemble as tetramers, with coassembly between subunits limited to four major families named AMPA, kainate, NMDA and delta receptors. Within each family, there are four AMPA receptor subunits, five kainate receptor subunits, seven NMDA receptor subunits, and two delta receptor subunits, which assemble in different combinations to generate various homomeric or heteromeric species in vivo. Functional experiments have shown that individual iGluR subtypes and their assemblies exhibit unique gating characteristics Traynelis et al.

    Key insights into the formation of tetrameric receptors were provided by iGluR crystal and cryo-EM structures.

    Thomas W. Abrams and Wayne Sossin

    The ATD and LBD, both of which combine as dimers with two-fold symmetry, can be genetically excised and individually expressed as soluble proteins; when crystallized, the soluble proteins form dimeric structures identical to those found in intact receptors Mayer, ; Furukawa, , motivating the study of their assembly using biophysical techniques. To gain insight into the energetics and specificity of iGluR assembly, multiple studies have used analytical ultracentrifugation AUC to examine the oligomerization of both the ATD and LBD expressed as soluble proteins, allowing analysis of both self-association and hetero-association processes in solution over a wide range of affinities.

    These studies revealed that the equilibrium dissociation constant K D for dimer assembly by the LBD is too weak to reliably measure Furukawa et al. In support, dimeric GluA2 assembly intermediates have been resolved by single-particle EM studies after synchronized protein expression, showing closely apposed ATD domains Shanks et al.

    Further, electrophysiological studies with ATD mutants have shown that ATD interactions are critical for the assembly of functional heteromeric receptors Kumar et al. On the other hand, additional important contributions in iGluR assembly are likely to arise from other interactions, including the transmembrane domain Gan et al.

    Currently the energetic contributions and importance of these domains relative to that of the ATD are not clear. The study of iGluR high-affinity homo- and hetero-associations was greatly facilitated in the last decade by the introduction of a commercial fluorescence detection system FDS for analytical ultracentrifugation MacGregor et al.

    However, the results were impacted by technical issues resulting from non-specific interactions due to the hydrophobic FAM label attached as an extrinsic fluorophore Rossmann et al. Using model systems, in subsequent studies we have systematically addressed these issues, identifying DyLight and EGFP as labels better suited for FDS experiments on iGluR ATDs, and have developed analytical procedures and controls that allow measurement of protein interactions with low pM equilibrium dissociation constants Zhao et al.

    Applied to GluA2 homodimerization Zhao et al. Experiments with recombinant receptors and genetically targeted mice also reveal that GluK1-GluK3 can coassemble to form functional heteromeric KaiRs Cui and Mayer, ; Mulle et al. Therefore, here we embark on a systematic study of the affinities of all KaiR homo- and heterodimers, and in addition use improved methods to revisit the interactions of AMPA receptor ATDs in a systematic survey of their homomeric and heteromeric binding affinities.

    We find distinct patterns of ATD assembly that differ between AMPA and kainate receptor families, with dissociation equilibrium constants spanning several orders of magnitude, revealing clearly energetically favored homomeric and heteromeric assemblies. Because mixtures of KaiR ATDs exhibit simultaneous and competitive homo-dimerization and hetero-dimerization equilibria, the strategy used for their analysis was to characterize their self-association first, such that the homo-dimerization K D can be fixed in the analysis of mixtures, which then can reveal the affinity of hetero-dimerization.

    For GluK1 and GluK2 we performed tracer titration experiments in which a series of concentrations of unlabeled protein was added to a low concentration of the labeled sample, shifting the sedimentation profile from monomer to dimer species. For GluK3, which expressed less well than other KaiR species, we performed a dilution series of the fluorescently labeled sample.

    GluK1 and GluK2 share the common pattern of a major peak, which shifts to higher sedimentation coefficients as the concentration increases over the range of 0. By contrast, although no concentration dependent shift in peak position is observed for either GluK3 Panel C or GluK4 Panel D the sedimentation coefficients for these species are strikingly different. For better visual comparison, s w is normalized to assign a value of 1. Because at the lowest concentrations studied, GluK3 did not dissociate into monomers, we did not study its association with other KaiR ATDs.


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    The s w isotherm calculated from this experiment Panel B was fit with a coupled equilibrium model, in which the K D and s -values for the two homo-dimerization reactions were fixed at values determined from independent measurements Figure 1 and Table 1 , while the K D and s -value for the heterodimer are refined. The best-fit heterodimer K D of 1. A GluK1 control sample without GluK2 grey is virtually superimposed by those for 0. Panel B: s w isotherm normalized to assign a value of 1. For all combinations studied, at the highest concentration of the unlabeled protein 1.

    For comparison, the dashed line shows the isotherm for homomeric GluK1. These were fit with a coupled equilibrium model in which the K D and s -values for the two homo-dimerization reactions were fixed at values determined from independent measurements as described above Figure 1 and Table 1 , with the K D and s -value for the heterodimer fit as free parameters.

    Neuropharmacology | 2014(10) articles

    As described above for kainate receptors, we first determined the K D and sedimentation coefficients for self-association of AMPA receptors ATDs, and then used these as constraints for analysis of heteromeric assemblies. For GluA1, a minor peak at 2. The 2. For comparison, the dotted and dashed lines show isotherms for GluA2 and GluA3, respectively.

    Value from Zhao et al. The homo-dimerization K D of GluA1 and GluA4 is in a range that provides correspondingly high fluorescence signals at concentrations that produce mixed populations of monomers and dimers. This exposes more details in terms of the kinetic stability of homo-dimers in the sedimentation patterns compared to data from titration series experiments which use low nM concentrations of a fluorescent label.

    This is characteristic for a monomer-dimer equilibrium with slow dissociation on the time-scale of sedimentation Dam et al. By contrast, for GluA4, the peak position shifts to intermediate values at concentrations of 50 and nM — similar to the behavior observed previously for GluA2 Zhao et al.

    To examine the assembly of AMPA receptor heterodimers we exploited a titration series strategy to monitor the oligomeric state of the fluorophore carrier as a function of concentration of its unlabeled binding partner. To facilitate accurate analysis of what we expected to be high affinity interactions, with dissociation constants in the nM range, for all AMPA receptor ATD pairs examined, a 0.

    As shown in Figure 5 the sedimentation coefficient distributions display predominantly monomeric species at low protein concentrations, shifting to predominantly dimeric species at high protein concentrations, indicating nearly full binding saturation. It should be noted that the s -values for the monomer, homo-dimer, as well as hetero-dimer species varies for individual pairs, depending on whether the fluorescent label was DyLight GluA2 or an EGFP fusion GluA1 and GluA3.

    Similar to kainate receptors, the hetero-dimerization affinity was determined by fitting a binding model describing the three coupled equilibria for which the K D and s -values for the two homo-dimerization reactions were fixed at pre-determined values described above, while refining the K D and s -value for the heterodimer.

    The results in Figure 6A highlight differences in affinity for heterodimers vs. Weighted-average s w as a function of concentration were extracted from the sedimentation coefficient distributions shown in Figure 5 , and fit with a competitive homo- and hetero-dimerization model using previously determined homo-dimerization parameters of both components as fixed constraints solid line.

    In the present work we have undertaken a systematic survey of homomeric and heteromeric kainate and AMPA receptor ATD dimer stabilities. On one hand, this can aid the interpretation of an increasing body of iGluR structural data and their dimerization interfaces Rossmann et al. The relative free energy of binding of purified receptor ATDs was hypothesized to reconstruct an assembly pathway and reflect the diversity in dimeric populations found in vivo Rossmann et al.

    In addition, interactions mediated by other receptor domains, especially the transmembrane domain Gan et al. However, knowledge of the relative thermodynamic stability of assembly of ATD dimers for different species forms a useful guide for the analysis of additional regulatory contributions. Further, at least at some stage of receptor assembly, without invoking as of yet unknown mechanisms, the formation of heterodimers would be directly competitive to the homodimers of their components, and therefore the comparison of their binding energetics and kinetics is of special interest.

    Of note, the GluA1 and GluA3 heterodimer assemblies with GluA2 exhibit K D -values that are 7-fold and fold lower than that for self-assembly of GluA2, indicating that heterodimer assembly is strongly preferred. In particular, the comparatively low stability of GluA3 homodimer leads to the strongest preference of GluA3 to hetero-dimerize. The color of the big circle energy cloud surrounding each pair indicates the free energy level of the dimerization, using the color temperature scale on the right.

    The width, line type, and color of the arrows emphasizes the stability difference between pairs with exchanged subunits. The dashed lines are visual guides for comparison, at the level of different homodimer free energies. We have hypothesized this largely to originate from artificial hydrophobic interfaces, which are eliminated in the present work by using DyLight labels carrying charged sulfonate groups, or EGFP fusion constructs Zhao et al.

    Another source of discrepancy arises from data processing not consistently based on rigorous mass transport theory to account for seemingly binding incompetent fractions Rossmann et al. Also, we found similar affinity for GluA1 and GluA2 homodimers, in contrast to fold difference observed from FAM-labeled preparations Rossmann et al. These differences are qualitatively important, for example, as they resolve the previously reported unexpectedly similar low nM K D -values for the GluA2 homodimer and the hetero-dimer assemblies with GluA1, GluA3 and GluA4 Rossmann et al.

    In this context we note the new kinetic results which for GluA2, GluA3, and GluA4 show at least an order of magnitude shorter homodimer lifetime as compared to GluA1, seemingly facilitating the pathway to form high-affinity heterodimers. Despite the similar homodimer affinities of GluA1 and GluA2, the on-rate constant is at least fold lower for GluA1, which may arise from differences in flexibility and subtle structural differences of the largely conserved homodimer interface comparing the two Yao et al.

    In general, AMPA receptors bind more tightly for both homo- and hetero-dimerization reactions. With the exception of GluK3, all homodimers were found to be relatively weak, which provides larger driving force to form heterodimers among kainate as compared to AMPA receptor ATDs. This suggests that similar guiding principles of subtype combination may exist for other iGluR families Rossmann et al. Interestingly, the gating properties of GluK3 are also unique with a low affinity for glutamate and Zn modulation that is absent in other KaiRs Swanson et al.

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