Ionotropic Glutamate Receptors
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<scene name='Ionotropic_Glutamate_Receptors/Tmd_opening/2'>The TMD</scene> has a pore structure that is nearly identical to that of the [[Potassium Channel]]. With complete four-fold symmetry, 16 helices form a <scene name='Ionotropic_Glutamate_Receptors/Tmd_pore/1'>precise pore</scene> through which cations can flow through. In the current, inhibitor bound structure, the <scene name='Ionotropic_Glutamate_Receptors/Tmd_pore_m3_cross/2'>M3 helices cross</scene> at a highly conserved <scene name='Ionotropic_Glutamate_Receptors/Sytanlaaf_motif/2'>SYTANLAAF motif</scene>, with Thr 617, Ala 621, and Thr 625 occluding the ion permeation pathway.<ref name="Sobo"/> The <scene name='Ionotropic_Glutamate_Receptors/Tmd_narrow/4'>narrowest part</scene> 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 <scene name='Ionotropic_Glutamate_Receptors/Tmd_narrow_ala_622/1'>Alanine 622</scene>, which is replaced with a threonine in the Lurcher mouse model mentioned previously. This mutation, which introduces a significantly bulkier residue, destabilizes the tight helix crossing associated with the closed state of the receptor, resulting in a constitutively open ion channel.<ref name="Sobo"/> | <scene name='Ionotropic_Glutamate_Receptors/Tmd_opening/2'>The TMD</scene> has a pore structure that is nearly identical to that of the [[Potassium Channel]]. With complete four-fold symmetry, 16 helices form a <scene name='Ionotropic_Glutamate_Receptors/Tmd_pore/1'>precise pore</scene> through which cations can flow through. In the current, inhibitor bound structure, the <scene name='Ionotropic_Glutamate_Receptors/Tmd_pore_m3_cross/2'>M3 helices cross</scene> at a highly conserved <scene name='Ionotropic_Glutamate_Receptors/Sytanlaaf_motif/2'>SYTANLAAF motif</scene>, with Thr 617, Ala 621, and Thr 625 occluding the ion permeation pathway.<ref name="Sobo"/> The <scene name='Ionotropic_Glutamate_Receptors/Tmd_narrow/4'>narrowest part</scene> 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 <scene name='Ionotropic_Glutamate_Receptors/Tmd_narrow_ala_622/1'>Alanine 622</scene>, which is replaced with a threonine in the Lurcher mouse model mentioned previously. This mutation, which introduces a significantly bulkier residue, destabilizes the tight helix crossing associated with the closed state of the receptor, resulting in a constitutively open ion channel.<ref name="Sobo"/> | ||
=====The Ligand Binding Domain===== | =====The Ligand Binding Domain===== | ||
- | <scene name='Ionotropic_Glutamate_Receptors/Lbd_opening/3'>The LBD</scene> is located just above the TMD and has an overall <scene name='Ionotropic_Glutamate_Receptors/Lbd_opening_two/2'>two-fold axis of symmetry</scene>. Within each LBD lies the so-called <scene name='Ionotropic_Glutamate_Receptors/Lbd_clamshell_open/1'>“clamshell”</scene>. This structure is responsible for <scene name='Ionotropic_Glutamate_Receptors/Lbd_clamshell_open_bound/1'>binding glutamate</scene> 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 <scene name='Ionotropic_Glutamate_Receptors/Binding/1'>tightly binding glutamate</scene> within the clamshell, are highly conserved. Glutamate binding causes a <scene name='Ionotropic_Glutamate_Receptors/Two/ | + | <scene name='Ionotropic_Glutamate_Receptors/Lbd_opening/3'>The LBD</scene> is located just above the TMD and has an overall <scene name='Ionotropic_Glutamate_Receptors/Lbd_opening_two/2'>two-fold axis of symmetry</scene>. Within each LBD lies the so-called <scene name='Ionotropic_Glutamate_Receptors/Lbd_clamshell_open/1'>“clamshell”</scene>. This structure is responsible for <scene name='Ionotropic_Glutamate_Receptors/Lbd_clamshell_open_bound/1'>binding glutamate</scene> 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 <scene name='Ionotropic_Glutamate_Receptors/Binding/1'>tightly binding glutamate</scene> within the clamshell, are highly conserved. Glutamate binding causes a <scene name='Ionotropic_Glutamate_Receptors/Two/2'>conformational change</scene> (<scene name='Ionotropic_Glutamate_Receptors/Two_top/1'>Alternate View</scene>) 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 <scene name='Ionotropic_Glutamate_Receptors/Morph_binding/3'>seen here</scene>. 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 and thus plays a more critical role in channel sensitization and activation.<ref name="Sobo"/> |
====Pharmaceutical Relevance==== | ====Pharmaceutical Relevance==== | ||
As mentioned previously, extensive investigation into the [[Pharmaceutical drugs|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 and anticonvulsants, small molecules that potentiate AMPA receptor currents have been proven to relieve cognitive deficits caused by neurodegenerative diseases such as [[Alzheimer's Disease]].<ref name="Purcel"/> Modulators such as aniracetam and CX614 **bind on the backside** 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.<ref name="Jin"/> | As mentioned previously, extensive investigation into the [[Pharmaceutical drugs|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 and anticonvulsants, small molecules that potentiate AMPA receptor currents have been proven to relieve cognitive deficits caused by neurodegenerative diseases such as [[Alzheimer's Disease]].<ref name="Purcel"/> Modulators such as aniracetam and CX614 **bind on the backside** 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.<ref name="Jin"/> |
Revision as of 03:57, 13 March 2011
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Additional Resources
For additional information on the Symmetry of the Glutamate Receptor, See: Glutamate Receptor Symmetry Analysis
For Additional Information, See: Membrane Channels & Pumps
For Additional Information, See: Alzheimer's Disease
References
- ↑ 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
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 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
- ↑ 3.0 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
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