Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9HLZ0)

• DTT Name: Glutamate receptor AMPA 2 (GRIA2)
• Synonyms: Glutamate receptor ionotropic, AMPA 2; Glutamate receptor 2; GluRK2; GluRB; GluR2; GluR-K2; GluR-B; GluR-2; GluA2; AMPAselective glutamate receptor 2; AMPA-selective glutamate receptor 2
• Gene Name: GRIA2
• DTT Type: Successful target; [1]
• BioChemical Class: Glutamate-gated ion channel
• UniProt ID: GRIA2_HUMAN
• TTD ID: T42392
• Sequence:
  MQKIMHISVLLSPVLWGLIFGVSSNSIQIGGLFPRGADQEYSAFRVGMVQFSTSEFRLTP
  HIDNLEVANSFAVTNAFCSQFSRGVYAIFGFYDKKSVNTITSFCGTLHVSFITPSFPTDG
  THPFVIQMRPDLKGALLSLIEYYQWDKFAYLYDSDRGLSTLQAVLDSAAEKKWQVTAINV
  GNINNDKKDEMYRSLFQDLELKKERRVILDCERDKVNDIVDQVITIGKHVKGYHYIIANL
  GFTDGDLLKIQFGGANVSGFQIVDYDDSLVSKFIERWSTLEEKEYPGAHTTTIKYTSALT
  YDAVQVMTEAFRNLRKQRIEISRRGNAGDCLANPAVPWGQGVEIERALKQVQVEGLSGNI
  KFDQNGKRINYTINIMELKTNGPRKIGYWSEVDKMVVTLTELPSGNDTSGLENKTVVVTT
  ILESPYVMMKKNHEMLEGNERYEGYCVDLAAEIAKHCGFKYKLTIVGDGKYGARDADTKI
  WNGMVGELVYGKADIAIAPLTITLVREEVIDFSKPFMSLGISIMIKKPQKSKPGVFSFLD
  PLAYEIWMCIVFAYIGVSVVLFLVSRFSPYEWHTEEFEDGRETQSSESTNEFGIFNSLWF
  SLGAFMQQGCDISPRSLSGRIVGGVWWFFTLIIISSYTANLAAFLTVERMVSPIESAEDL
  SKQTEIAYGTLDSGSTKEFFRRSKIAVFDKMWTYMRSAEPSVFVRTTAEGVARVRKSKGK
  YAYLLESTMNEYIEQRKPCDTMKVGGNLDSKGYGIATPKGSSLRNAVNLAVLKLNEQGLL
  DKLKNKWWYDKGECGSGGGDSKEKTSALSLSNVAGVFYILVGGLGLAMLVALIEFCYKSR
  AEAKRMKVAKNAQNINPSSSQNSQNFATYKEGYNVYGIESVKI
• Function: L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. Through complex formation with NSG1, GRIP1 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission.
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocannabinoid signaling (hsa04723)
  Glutamatergic synapse (hsa04724)
  Dopaminergic synapse (hsa04728)
  Long-term depression (hsa04730)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  Long-term potentiation (R-HSA-9620244)
  Activation of AMPA receptors (R-HSA-399710)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
E-2007	DMJDYNQ	Diabetic neuropathy	8C0Z	Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Paliroden	DMX8ZAQ	Parkinson disease	8A00.0	Phase 2	[2]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-5-fluorowillardiine	DMCIZ7P	Discovery agent	N.A.	Investigative	[3]
ATPO	DMXLS78	Discovery agent	N.A.	Investigative	[3]
[3H]AMPA	DMLF7SG	N. A.	N. A.	Investigative	[3]
[3H]CNQX	DMIFKUX	Discovery agent	N.A.	Investigative	[3]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Parkinson's disease	8A00.0	Substantia nigra tissue	8.57E-01	-0.08	-0.14

References

• [1] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [2] Mechanism of inhibition of the GluA2 AMPA receptor channel opening by talampanel and its enantiomer: the stereochemistry of the 4-methyl group on the diazepine ring of 2,3-benzodiazepine derivatives.ACS Chem Neurosci.2013 Apr 17;4(4):635-44.
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 445).