Sandbox Reserved 1649: Difference between revisions
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'''Ligand binding domain (LBD)''' | '''Ligand binding domain (LBD)''' | ||
LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of amino-group of the agonist | LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of amino-group of the agonist binds to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/1'>D213</scene>) is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/1'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/1'>E14</scene>).<scene name='86/868182/Y243_et_e14/1'>Click here if you want to see E14 and Y243 together</scene>. The high affinity for glutamate agonist may be because of van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/1'>T114</scene> and <scene name='86/868182/S112/1'>S112</scene>. <scene name='86/868182/T114_et_s112/1'>(T114 and S112 together)</scene> | ||
On the other hand, <scene name='86/868182/Aa_in_interaction_with_nr1/1'>amino acids</scene> from this domain interact with NR1 (see NR1/NR2A complex part). | On the other hand, <scene name='86/868182/Aa_in_interaction_with_nr1/1'>amino acids</scene> from this domain interact with NR1 (see NR1/NR2A complex part). | ||
'''Transmembrane domain''' | '''Transmembrane domain''' | ||
The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization.<ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref> | The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization.<ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref> | ||
M2 loop is a channel-lining loop and located in transmembrane domain. Two asparagines are located on N site of the domain and block Mg2+ and are permeable of Ca2+ <ref name="M2loop">DOI 10.3390/ijms21041538</ref> | M2 loop is a channel-lining loop and located in transmembrane domain. Two asparagines are located on N site of the domain and block Mg2+ and are permeable of Ca2+ <ref name="M2loop">DOI 10.3390/ijms21041538</ref> | ||
Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref> | Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref> | ||
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'''CTD''' | '''CTD''' | ||
CTD domain is the less conserved of NR2 domain and like ATD allows | CTD domain is the less conserved of NR2 domain and like ATD allows different localization of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable to receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD. <ref name="M2loop"/> | ||
== Regulation == | == Regulation == | ||
A high quantity of stress can lead to | A high quantity of stress can lead to the overactivation of NMDA receptors. Therefore, a regulation can occur on NMDA receptors in order to avoid any neuronal injury. This very important regulation can act at the level of NR2A subunit. | ||
For now, scientists know that regulation can occur in several ways: either a modification directly affects the functioning of the receptor, or the quantity of receptors at the surface of the neuron by modifying NR2A itself or not. | For now, scientists know that regulation can occur in several ways: either a modification directly affects the functioning of the receptor, or the quantity of receptors at the surface of the neuron by modifying NR2A itself or not. | ||
• Inhibition by Zn2+ | '''• Inhibition by Zn2+ ''' | ||
Zn2+ exercises a control on the functioning of NR2A. Zn2+ is considered to be an endogenous inhibitor of NMDA receptors. Indeed, the NTD of NR2A subunit forms a binding site for Zn2+. | Zn2+ exercises a control on the functioning of NR2A. Zn2+ is considered to be an endogenous inhibitor of NMDA receptors. Indeed, the NTD of NR2A subunit forms a binding site for Zn2+. | ||
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'''• Inhibition by CK2 indirectly on NR2A''' | |||
• Inhibition by CK2 indirectly on NR2A | |||
Casein Kinase 2 (CK2) determines the NR2 subunit content of synaptic NMDA. Indeed, CK2 phosphorylates NR2B subunit in response to activity, what regulates the number of synaptic NR2A and NR2B. Indeed, CK2 phosphorylation leads to NR2B endocytosis and remove NR2B from synapses, resulting in an increase in synaptic NR2A expression. | Casein Kinase 2 (CK2) determines the NR2 subunit content of synaptic NMDA. Indeed, CK2 phosphorylates NR2B subunit in response to activity, what regulates the number of synaptic NR2A and NR2B. Indeed, CK2 phosphorylation leads to NR2B endocytosis and remove NR2B from synapses, resulting in an increase in synaptic NR2A expression. | ||
• Inhibition by palmitoylation directly on NR2A | '''• Inhibition by palmitoylation directly on NR2A''' | ||
NR2A has two distinct consensus cysteine clusters in its C-terminal region, which are susceptible to be palmitoylated. | NR2A has two distinct consensus cysteine clusters in its C-terminal region, which are susceptible to be palmitoylated. | ||
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== NR1/NR2A complex == | == NR1/NR2A complex == | ||
NR2A can be found in some NMDA receptors, in which NR2A is associated to NR1. NMDA receptors are necessarily heteromers of 4 subunits, organized as a dimer of dimers. These dimers are heterodimers constituted with glycine binding NR1 and glutamate binding subunits NR2. | NR2A can be found in some NMDA receptors, in which NR2A is associated to NR1. NMDA receptors are necessarily heteromers of 4 subunits, organized as a dimer of dimers. These dimers are heterodimers constituted with glycine binding NR1 and glutamate binding subunits NR2. | ||
