Dynamics and allosteric potential of the AMPA receptor N-terminal domain

Sukumaran, Madhav; Rossmann, Maxim; Shrivastava, Indira H.; Dutta, Anindita; Bahar, İvet; Greger, Ingo H.

doi:10.1038/emboj.2011.17

Cited by 56 publications

(119 citation statements)

References 69 publications

(134 reference statements)

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“…Similarly, the second extracellular portion, the N-terminal domain (NTD), crystallized as a dimer, in both AMPA and kainate receptors (Fig. 11.1b) (Clayton et al 2009;Jin et al 2009;Kumar et al 2009;Karakas et al 2009;Kumar and Mayer 2010;Sukumaran et al 2011). This overall twofold symmetry of the extracellular portion is also observed at the level of the intact receptor, whereas the ion channel adopts fourfold symmetry ).…”

Section: Dimer Formationmentioning

confidence: 83%

AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

Sukumaran

Penn

Greger

2012

Advances in Experimental Medicine and Biology

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Glutamate-gated ion channels (iGluRs) predominantly operate as heterotetramers to mediate excitatory neurotransmission at glutamatergic synapses. The subunit composition of the receptors determines their targeting to synaptic sites and signalling properties and is therefore a fundamental parameter for neuronal computations. iGluRs assemble as obligatory or preferential heteromers; the mechanisms underlying this selective assembly are only starting to emerge. Here we review recent work in the field and provide an in-depth update on atomic determinants in the assembly domains, which have been facilitated by recent advances in iGluR structural biology. We also discuss the role of alternative RNA processing in the ligand-binding domain, which modulates a central subunit interface and has the capacity to modulate receptor formation in response to external cues. Finally, we review the emerging physiological significance of signalling via distinct iGluR heterotetramers and provide examples of how recruitment of functionally diverse receptors modulates excitatory neurotransmission under physiological and pathological conditions.

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Section: Dimer Formationmentioning

confidence: 83%

AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

Sukumaran

Penn

Greger

2012

Advances in Experimental Medicine and Biology

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“…This preference appears to be an intrinsic property of GluA1 and GluA2 sequences because changing SPs do not affect the linear I-V curves. Previous studies demonstrated that heterodimers could be formed both in isolated ATDs of GluA2 and GluA3 (39,40) and in kainate receptors (20,41). The velocity sedimentation study of isolated ATDs shows that the heterodimer of GluA1/A2 ATDs has the smallest dissociation constant (K d ); thus, the heterodimers are preferred (31).…”

Section: Discussionmentioning

confidence: 99%

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Kalyanaraman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in fulllength GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.AMPA receptors | signal peptide | spatial assembly | stoichiometry

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“…In fact, crystal structures of the Zn 2ϩ -bound and free NTD of the GluN2B subunit indicate that the NTD also favors a closed conformation in the absence of Zn differs from that in NMDA receptors, and a significant closure of the putative ligand-binding cleft in the AMPA receptor NTD is thought to be unlikely. AMPA receptor NTDs have, however, been shown to display flexibility (a prerequisite for an allosteric role), ranging from large-scale domain movements to more subtle conformational fluctuations (6,8,(53)(54)(55). A wide range of NTD conformations, some differing substantially from the arrangement in GluA2 cryst, have been reported on the basis of electron microscopic (16, 53, 56 -58) and atomic force microscopic (55) analyses of purified AMPA and kainate receptor preparations, supporting the view that the NTD can assume different conformations, at least under the specific experimental conditions used.…”

Section: Discussionmentioning

confidence: 99%