1.A.10.1.20 Heteromeric ionotropic NMDA receptor (NMDAR) consisting of two subunits, GluN1 (938 aas) and GluN2A (1464 aas). Positions of the Mg2+ and Ca2+ ions in the ion channel divalent cation binding site have been proposed, and differences in the structural and dynamic behavior of the channel proteins in the presence of Mg2+ or Ca2+ have been analyzed (Mesbahi-Vasey et al. 2017). GRIN variants in receptor M2 channel pore-forming loop are associated with neurological diseases (Li et al. 2019). Disease-associated variants have revealed mechanistic aspect of the NMDA receptor (Amin et al. 2021). Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors (Iacobucci et al. 2021). The gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors have been reported (Wang et al. 2021). GluN2A and GluN2B NMDA receptors apparently use distinct allosteric routes (Tian et al. 2021). A negative allosteric modulatory site in the GluN1 M4 determines the efficiency of neurosteroid modulation (Langer et al. 2021). Excitatory signaling mediated by NMDAR is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs can be used for treating depression, Alzheimer's disease, and epilepsy. Chou et al. 2022 monitored the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site. The channel blockers form interactions with pore-lining residues, which control mostly off-speeds but not on-speeds (Chou et al. 2022). NMDAR channel blockers include MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration (Wilcox et al. 2022). Pregnane-based steroids are positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations (Kysilov et al. 2022). The NMDA receptor C-terminal domain signals in development, maturity, and disease (Haddow et al. 2022). Blood tissue Plasminogen Activator (tPA) of
liver origin contributes to neurovascular coupling involving brain
endothelial N-Methyl-D-Aspartate (NMDA) receptors (Furon et al. 2023). Two gates mediate NMDA receptor activity and are under subunit-specific regulation (Amin et al. 2023). One of the main molecular mechanisms of ketamine action is the blockage of NMDA-activated glutamate receptors (Pochwat 2022). The S1-M1 linker of the NMDA receptor controls channel opening (Xie et al. 2023).
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Accession Number: | Q12879 |
Protein Name: | Glutamate receptor ionotropic, NMDA 2A |
Length: | 1464 |
Molecular Weight: | 165283.00 |
Species: | Homo sapiens (Human) [9606] |
Number of TMSs: | 4 |
Location1 / Topology2 / Orientation3: |
Cell membrane1 / Multi-pass membrane protein2 |
Substrate |
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1: MGRVGYWTLL VLPALLVWRG PAPSAAAEKG PPALNIAVML GHSHDVTERE LRTLWGPEQA
61: AGLPLDVNVV ALLMNRTDPK SLITHVCDLM SGARIHGLVF GDDTDQEAVA QMLDFISSHT
121: FVPILGIHGG ASMIMADKDP TSTFFQFGAS IQQQATVMLK IMQDYDWHVF SLVTTIFPGY
181: REFISFVKTT VDNSFVGWDM QNVITLDTSF EDAKTQVQLK KIHSSVILLY CSKDEAVLIL
241: SEARSLGLTG YDFFWIVPSL VSGNTELIPK EFPSGLISVS YDDWDYSLEA RVRDGIGILT
301: TAASSMLEKF SYIPEAKASC YGQMERPEVP MHTLHPFMVN VTWDGKDLSF TEEGYQVHPR
361: LVVIVLNKDR EWEKVGKWEN HTLSLRHAVW PRYKSFSDCE PDDNHLSIVT LEEAPFVIVE
421: DIDPLTETCV RNTVPCRKFV KINNSTNEGM NVKKCCKGFC IDILKKLSRT VKFTYDLYLV
481: TNGKHGKKVN NVWNGMIGEV VYQRAVMAVG SLTINEERSE VVDFSVPFVE TGISVMVSRS
541: NGTVSPSAFL EPFSASVWVM MFVMLLIVSA IAVFVFEYFS PVGYNRNLAK GKAPHGPSFT
601: IGKAIWLLWG LVFNNSVPVQ NPKGTTSKIM VSVWAFFAVI FLASYTANLA AFMIQEEFVD
661: QVTGLSDKKF QRPHDYSPPF RFGTVPNGST ERNIRNNYPY MHQYMTKFNQ KGVEDALVSL
721: KTGKLDAFIY DAAVLNYKAG RDEGCKLVTI GSGYIFATTG YGIALQKGSP WKRQIDLALL
781: QFVGDGEMEE LETLWLTGIC HNEKNEVMSS QLDIDNMAGV FYMLAAAMAL SLITFIWEHL
841: FYWKLRFCFT GVCSDRPGLL FSISRGIYSC IHGVHIEEKK KSPDFNLTGS QSNMLKLLRS
901: AKNISSMSNM NSSRMDSPKR AADFIQRGSL IMDMVSDKGN LMYSDNRSFQ GKESIFGDNM
961: NELQTFVANR QKDNLNNYVF QGQHPLTLNE SNPNTVEVAV STESKANSRP RQLWKKSVDS
1021: IRQDSLSQNP VSQRDEATAE NRTHSLKSPR YLPEEMAHSD ISETSNRATC HREPDNSKNH
1081: KTKDNFKRSV ASKYPKDCSE VERTYLKTKS SSPRDKIYTI DGEKEPGFHL DPPQFVENVT
1141: LPENVDFPDP YQDPSENFRK GDSTLPMNRN PLHNEEGLSN NDQYKLYSKH FTLKDKGSPH
1201: SETSERYRQN STHCRSCLSN MPTYSGHFTM RSPFKCDACL RMGNLYDIDE DQMLQETGNP
1261: ATGEQVYQQD WAQNNALQLQ KNKLRISRQH SYDNIVDKPR ELDLSRPSRS ISLKDRERLL
1321: EGNFYGSLFS VPSSKLSGKK SSLFPQGLED SKRSKSLLPD HTSDNPFLHS HRDDQRLVIG
1381: RCPSDPYKHS LPSQAVNDSY LRSSLRSTAS YCSRDSRGHN DVYISEHVMP YAANKNNMYS
1441: TPRVLNSCSN RRVYKKMPSI ESDV