Ionotropic Glutamate Receptors

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Revision as of 09:51, 18 August 2014

spinqualitylabelsall models Structure of the ionotropic glutamate receptor tetramer, GluA2, (3kg2) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image       Ionotropic Glutamate Receptors (IGluRs) are a family of ligand-gated ion channels that are responsible for fast excitatory neurotransmission.[1] Primarily localized to nerve synapses in mammals, IGluRs are implicated in nearly all aspects of nervous system development and function.[2] Synapses form the connection between two neuronal cells. Within synapses, neurotransmitters are released from vesicles in presynaptic cells and interact with receptors in postsynaptic cells to allow for communication between nerve cells.[1] Glutamate is the predominant neurotransmitter of excitatory synapses and interacts specifically with AMPA and NMDA IGluRs.[3] Additional details in Molecular Playground/Glutamate Receptor Metabotropic glutamate receptor Glutamate receptor (GluA2) Neurodevelopmental Disorders Ligand Binding N-Terminal of Metabotropic Glutamate Receptors. Contents 1 Involvement in Autism Spectrum Disorders 2 GluA2 Structure 2.1 The Amino Terminal Domain 2.2 The Transmembrane Domain 2.3 The Ligand Binding Domain 3 Pharmaceutical Relevance Involvement in Autism Spectrum Disorders       Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders. During development, glutamate regulates neuronal growth and synaptogenesis, effectively dictating the underlying connective neuronal architecture of the brain.[3] Significant research into ASDs has been devoted to understanding how glutamate receptors function and how disruption leads to neurodevelopmetnal disorders. IGluRs are concentrated in regions of the brain that have been implicated in ASDs including the cerebellum and hippocampus. These are the areas responsible for motor control, spatial navigation and memory, attributes that are often disrupted in patients with ASDs. Studies have revealed that glutamate receptor expression is increased in the cerebellum of autistic individuals by nearly 250%. A number of small nucleotide polymorphisms in IGluRs have also been identified which correlate with the ASDs. Further, many people with autism have clearly visible disturbances in the inferior olive (IO) in the brain. The IO plays a critical role in movement coordination and maintenance of an underlying 12 Hz brain rhythm through careful regulation of glutamate signaling.[4] A well-known mouse model called “Lurcher” for the lurching type movements the mice make has served as an important model for studying ASDs. The mutation that causes the “Lurcher” phenotype creates a constitutively leaky glutamate receptor ion channel resulting in IO neuron degeneration and loss of purkinje cells. These mice exhibit some of the well-known Autism-like characteristics.[5] Such relationships between overly active glutamate receptors leading to increased excitation/inhibition ratios and autism have led some to propose using glutamate receptor inhibitors as a means of pharmaceutical intervention for improving those with autistic symptoms.[6] Many pharmacological agents that reduce neural excitation, such as benzodiazapines, are thought to potentially have therapeutic value in treating autistic symptoms.[3] GluA2 Structure       AMPA IGluRs form composed of and . Each subunit includes an extracellular (ATD) which is responsible for receptor trafficking within the membrane, a (LBD) which activates the receptor upon binding glutamate, and a (TMD) which forms the membrane-spanning ion channel. Also present is a carboxy-terminal domain involved in receptor localization and regulation, although the structure of this domain has not been solved.[2] The structure of AMPA IGluRs or in this case GluA2, is unique in that the . The ATD has a local two-fold symmetry, the LBD has a two-fold symmetry, while the TMD has a four-fold symmetry. Here is a morph depicting the . This symmetry mismatch has implications for function of the receptor with subunits behaving differently depending upon their orientation despite identical primary sequence.[2] For an excellent analysis, see: Glutamate Receptor Symmetry Analysis The Amino Terminal Domain       is responsible for receptor assembly, trafficking and localization. It has two unique sets of interactions which hold the tetramer together. The is present in each pair of dimers and involves both hydrogen bonding and hydrophobic interactions. The , which includes residues Ile 203, Thr 204, Ile 205, and Val 209 on both chains among others, effectively holds the pair of dimers together at an angle that is roughly 24 degrees off of the overall two-fold axis.[2][7] The Transmembrane Domain       has a pore structure that is nearly identical to that of the Potassium Channel. With complete four-fold symmetry, 16 helices form a through which cations can flow through. In the current, inhibitor bound structure, the at a highly conserved , with Thr 617, Ala 621, and Thr 625 occluding the ion permeation pathway.[2] The of the channel includes the residues Thr 625, Ala 621, and Thr 617, but does not distinguish between positive cations like in the Potassium Channel. Located next to this narrow region lies , which is replaced with a threonine in the Lurcher mouse model mentioned previously. This mutation, which introduces a much bulkier residue, prevents the helices from closing properly, resulting in a constitutively open ion channel.[2] The Ligand Binding Domain       is located just above the TMD and has an overall . Within each LBD lies the so-called . This structure is responsible for and “sensitizing” the receptor to allow passage of cations through the channel. Residues Pro 89, Leu 90, Arg 96, Ser 142, & Glu 193 among others (residue numbers in 1ftj model), which are responsible for within the clamshell, are highly conserved. Glutamate binding causes a () in the LBD which pulls the M3 helices in the TMD apart, opening the channel and allowing for cation passage. A morph of the conformational change in the LBD upon glutamate binding can be . Uniquely, due to the varied importance of the homotetramer subunits due to symmetry mismatch, the interaction of glutamate with the distal subunits is predicted to result in a greater conformational change. Thus these distal subunits play a more critical role in channel sensitization and activation.[2] Pharmaceutical Relevance       As mentioned previously, extensive investigation into the pharmaceutical potential of IGluRs as a target for treating various ailments including Autism Spectrum Disorders symptoms is ongoing. In addition to agents which reduce neural excitation such as benzodiazapines, small molecules that potentiate AMPA receptor currents have been proven to reduce cognitive deficits caused by neurodegenerative diseases such as Alzheimer's Disease.[3] Modulators such as aniracetam and CX614 (2al4) of the ligand-binding core through interactions with a “proline ceiling” and a “serine floor”, stabilizing the closed-clamshell conformation. Although these compounds would likely be ineffective in the case of Autism patients because they slow the deactivation of the IGluR channels, this class of compounds has exciting therapeutic potential.[1]

Page Development

This article was developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.

3D structures of glutamate receptor

Updated on 18-August-2014

Topic Page on Glutamate Receptor GluA2 structure

There is a topic page describing in detail the GluA2 structure described in 3kg2. The page is meant to complement the original publication of the structure by Sobolevsky et al.^[2][8] with matching colors, etc..

Ionotropic glutamate receptor 0

2pyy - IGluR2 ligand-binding domain + Glu – Nostoc punctiforme

Ionotropic glutamate receptor 1

3saj - rIGluR1 N-terminal domain – rat

Ionotropic glutamate receptor 2

3n6v, 3o2j - rIGluR2 N-terminal domain (mutant) – rat
3hsy, 3h5v, 3h5w - rIGluR2 N-terminal domain
2wjw, 2wjx – hIGluR2 N-terminal domain - human
3rn8, 3rnn – hIGluR2 ligand-binding domain + potentiator
3bki - rIGluR2 ligand-binding domain + inhibitor
1fto, 4h8j - rIGluR2 ligand-binding domain
3t93 - rIGluR2 ligand-binding domain (mutant)

GluR2 positive allosteric modulator complex

2xhd - hIGluR2 ligand-binding domain + positive allosteric modulator + Glu
2al4, 1p1o - rIGluR2 ligand-binding domain (mutant) + positive allosteric modulator
2xx8, 2xx7, 2xx9, 2xxh, 2xxi, 3lsf, 3h6t, 3h6u, 3h6v, 3h6w, 3bbr, 3tkd, 4fat, 4iy5, 4iy6, 4lz5, 4lz7, 4lz8, 4n07 - rIGluR2 ligand-binding domain (mutant) + positive allosteric modulator + Glu
3pmv, 3pmw, 3pmx, 3o28, 3o29, 3o2a, 3o6g, 3o6h, 3o6i, 3m3l, 3lsl, 3tdj - rIGluR2 ligand-binding domain + positive allosteric modulator + Glu
1mm6, 1mm7 - rIGluR2 ligand-binding domain + positive allosteric modulator
3ijo, 3ijx, 3ik6, 3il1, 3ilt, 3ilu - rIGluR2 + positive allosteric modulator + Glu

GluR2 antagonist complex

3r7x - hIGluR2 + antagonist
3kgc, 3kg2, 2cmo - rIGluR2 ligand-binding domain + antagonist + Glu
A topic page describing in detail the GluA2 structure described in 3kg2
3h03, 3h06, 3b7d, 1n0t, 1ftl, 3tza, 3ua8, 4isu - rIGluR2 ligand-binding domain + antagonist
1lb9, 4l17 - rIGluR2 ligand-binding domain (mutant) + antagonist

GluR2 agonist complex

3rtf, 3rtw, 3pd8, 3pd9, 3bft, 3bfu, 1wvj, 1syh, 1syi, 1ms7, 1mqd, 1nnp, 1nnk, 1m5b, 1m5c, 1m5d, 1m5e, 1m5f, 1ftm, 4g8m, 4igt - rIGluR2 ligand-binding domain + agonist
3b6t, 2al5, 2anj, 1p1q, 1p1u, 1p1w, 1lb8 - rIGluR2 ligand-binding domain (mutant) + agonist
1lbc - rIGluR2 ligand-binding domain (mutant) + agonist + Glu
2p2a - rIGluR2 ligand-binding domain + agonist + Glu

GluR2 partial agonist complex

1y1m, 2aix, 1y1z, 1y20, 1mqg, 1mqh, 1mqi, 1mqj, 1mxu, 1mxv, 1mxw, 1mxx, 1mxy, 1mxz, 1my0, 1my1, 1my2, 1my3, 1my4, 1fw0, 1ftk, 1gr2 - rIGluR2 ligand-binding domain + partial agonist
1xhy, 1p1n, 1lbb, 3t96, 3t9h, 3t9u, 3t9v - rIGluR2 ligand-binding domain (mutant) + partial agonist

GluR2 ligand complex

3dp6, 2uxa, 2i3v, 2i3w, 1ftj - rIGluR2 ligand-binding domain + Glu
3b6q, 3b6w, 2gfe, 3t9x - rIGluR2 ligand-binding domain (mutant) + Glu
4gxs - rIGluR2 ligand-binding domain + kainate derivative

Ionotropic glutamate receptor 3

3o21, 3p3w – rIGluR3 N-terminal domain
3m3k – rIGluR3 ligand-binding domain
3rt6, 3rt8, 3dp4 – rIGluR3 ligand-binding domain + agonist
3m3f – rIGluR3 ligand-binding domain + allosteric modulator
3dln - rIGluR3 ligand-binding domain + Glu
4f1y - rIGluR3 ligand-binding domain + CNQX
4f22, 4f39, 4f3g - rIGluR3 ligand-binding domain + kainate
4f31 - rIGluR3 ligand-binding domain (mutant) + kainate
4f29 - rIGluR3 ligand-binding domain + quisqualate
4f2o, 4f2q - rIGluR3 ligand-binding domain (mutant) + quisqualate
4f3b - rIGluR3 ligand-binding domain (mutant) + Glu

Ionotropic glutamate receptor 4

3epe, 3fas - rIGluR4 ligand-binding domain + Glu
3kei – rIGluR4 ligand-binding domain (mutant) + Glu
3kfm - rIGluR4 ligand-binding domain (mutant) + partial agonist
3en3 - rIGluR4 ligand-binding domain + partial agonist
3fat – rIGluR4 ligand-binding domain + agonist
4gpa – rIGluR4 N terminal domain

Ionotropic glutamate receptor 5

3fuz, 2zns – hIGluR5 ligand-binding domain + Glu
1txf - rIGluR5 ligand-binding domain + Glu
2ojt - rIGluR5 + anion
3fv1, 3fv2, 3fvg, 3fvk, 3fvn, 3fvo, 2znt, 2znu - hIGluR5 ligand-binding domain + agonist
3c31, 3c32, 3c33, 3c34, 3c35, 3c36 - rIGluR5 ligand-binding domain + ion
2wky, 3gba, 3gbb, 2pbw, 2f34, 2f35, 2f36 – rIGluR5 ligand-binding domain + agonist
2qs1, 2qs2, 2qs3, 2qs4 - rIGluR5 ligand-binding domain (mutant) + agonist
1vso - rIGluR5 ligand-binding domain + antagonist

Ionotropic glutamate receptor 6

3h6g, 3h6h – rIGluR6 N-terminal domain
3g3f, 1sd3, 1s50, 1s7y – rIGluR6 ligand-binding domain + Glu
3g3g, 3g3h, 3g3i, 3g3j, 3g3k, 2i0b, 2i0c - rIGluR6 ligand-binding domain (mutant) + Glu
1s9t – rIGluR6 ligand-binding domain + positive allosteric modulator
1tt1 – rIGluR6 ligand-binding domain + partial agonist

Metabotropic glutamate receptor

Metabotropic glutamate receptor

Ionotropic kainate receptor 1

1ycj – rGluK1 ligand-binding domain + Glu
3s2v, 4dld – rGluK1 ligand-binding domain + antagonist
4e0x – rGluK1 ligand-binding domain + kainate

Ionotropic kainate receptor 2

2xxr – rGluK2 ligand-binding domain + Glu
4h8i - rGluK2 ligand-binding domain + Glu derivative
2xxu, 2xxx, 2xxw, 4bdl, 4bdn, 4bdq – rGluK2 ligand-binding domain (mutant) + Glu
4bdm, 4bdo, 4bdr – rGluK2 ligand-binding domain (mutant) + kainate
2xxt – rGluK2 ligand-binding domain + partial agonist
2xxv, 2xxy – rGluK2 ligand-binding domain (mutant) + partial agonist
3qlt - rGluK2 residues 32-420 (mutant)
1yae - rGluK2 ligand-binding domain + agonist
3qxm - hGluK2 ligand-binding domain + toxin

Ionotropic kainate receptor 3

3olz – rGluK3 N-terminal domain
3s9e, 3u93, 3u94, 4mh5 – rGluK3 ligand-binding domain + Glu
3u92, 4e0w - rGluK3 ligand-binding domain + kainate
4g8n, 4igr - rGluK3 ligand-binding domain + agonist

Ionotropic kainate receptor 5

3om0, 3om1 – rGluK5 N-terminal domain
3qlu - rGluK5 + rGluK2 (mutant)
3qlv - rGluK5 + rGluK2

NMDA receptor

3jpy, 3jpw – rNMDA subunit ε2 N-terminal domain (mutant)
2a5t - rNMDA subunits NR1 and NR2A ligand-binding domains
2a5s - rNMDA subunits NR1 and NR2A ligand-binding domains + Glu
3qek – XlNMDA subunit GLUN1 N terminal (mutant) – Xenopus laevis
3qel, 3qem – XlNMDA subunit GLUN1 N terminal (mutant) + rNMDA subunit ε2 N-terminal domain (mutant) + ifenprodil
4kcc – rNMDA 1 ligand-binding domain
4jwy – rNMDA 2D ligand-binding domain + agonist
4kcd – rNMDA 3A ligand-binding domain
4kfq – rNMDA 1 ligand-binding domain + antagonist
4nf4, 4nf5, 4nf6, 4nf8 – rNMDA 1 ligand-binding domain + rNMDA 2A ligand-binding domain (mutant)

See Also

• Glutamate Receptor Symmetry Analysis
  
• Glutamate receptor (GluA2) structure in detail
  
• Metabotropic glutamate receptor
  
• Membrane Channels & Pumps
  
• Alzheimer's Disease
  

References

1. ↑ ^{1.0 1.1 1.2} Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM. Mechanism of positive allosteric modulators acting on AMPA receptors. J Neurosci. 2005 Sep 28;25(39):9027-36. PMID:16192394 doi:25/39/9027
2. ↑ ^{2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7} Sobolevsky AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009 Dec 10;462(7274):745-56. Epub . PMID:19946266 doi:10.1038/nature08624
3. ↑ ^{3.0 3.1 3.2 3.3} Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001 Nov 13;57(9):1618-28. PMID:11706102
4. ↑ Welsh JP, Ahn ES, Placantonakis DG. Is autism due to brain desynchronization? Int J Dev Neurosci. 2005 Apr-May;23(2-3):253-63. PMID:15749250 doi:10.1016/j.ijdevneu.2004.09.002
5. ↑ Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N. Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature. 1997 Aug 21;388(6644):769-73. PMID:9285588 doi:10.1038/42009
6. ↑ Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003 Oct;2(5):255-67. PMID:14606691
7. ↑ Jin R, Singh SK, Gu S, Furukawa H, Sobolevsky AI, Zhou J, Jin Y, Gouaux E. Crystal structure and association behaviour of the GluR2 amino-terminal domain. EMBO J. 2009 Jun 17;28(12):1812-23. Epub 2009 May 21. PMID:19461580 doi:10.1038/emboj.2009.140
8. ↑ Wollmuth LP, Traynelis SF. Neuroscience: Excitatory view of a receptor. Nature. 2009 Dec 10;462(7274):729-31. PMID:20010675 doi:10.1038/462729a