Glutamate Receptors (Ion Channel Family)

The ion channel family of glutamate receptors ( ionotropic; glutamate receptors or iGluR) comprises three major subtypes based on pharmacology and protein structure. 

The N-methyl-D-aspartate (NMDA) subtype is a hetero-oligomer consisting of an NR1 subunit combined with one or more NR2 (A-D) subunits and a third subunit, NR3 (A,B). The receptor has two amino acid recognition sites, one for glutamate and one for glycine, both of which must be occupied to promote channel opening. Antagonists have been discovered which selectively compete for either the glutamate or glycine site, and these act as functional receptor antagonists. The channel is permeable to cations, including calcium, and is blocked by magnesium at membrane potentials close to resting, endowing a voltage dependence to this ligand-gated ion channel which is important for its physiological role as a " conditional" receptor. A variety of drugs have been identified which block the channel selectively. Other sites exist on the receptor through which polyamines, zinc, protons and oxidizing/reducing agents influence receptor function. Several classes of compounds have been identified that interact selectively with NMDA receptors containing NR2B, providing "subunit-selective" antagonists. The NMDA receptor is recognized as part of a large complex of cell surface proteins, receptors and intracellular mediators at the post-synaptic density, which interact to regulate excitatory neurotransmission and synaptic plasticity.

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype is a hetero-oligomer formed from combinations of iGluR1-4. Selective agonists and competitive antagonists acting at the glutamate recognition site have been useful for defining the physiological and pathophysiological roles played by the receptor. Allosteric sites on the receptor mediate the effects of the AMPAkines that potentiate the response to glutamate while GYKI 52466 and related compounds act as non-competitive inhibitors. The ion channel is cation-permeable, but calcium permeability is regulated by an RNA editing mechanism in the iGluR2 subunit. Joro spider toxin blocks the channel of AMPA receptors that do not contain the GluR2 subunit.

The kainate subtype consists of hetero-oligomers, comprising the iGluR5-7 and KA1 and KA2 subunits. Kainate itself and the AMPA analog ATPA have been used as selective agonists and recently, several competitive antagonists with selectivity for kainate receptors, particularly those containing iGluR5 subunits, have been identified.

The physiological and pathophysiological roles of ionotropic glutamate receptors have been extensively studied with both molecular and pharmacological approaches. NMDA receptors are post-synaptic and play important roles in plasticity in the developing and mature CNS and post-synaptic AMPA receptors mediate chemical transmission at the majority of fast excitatory synapses in the CNS. Both NMDA and AMPA receptors play key roles in certain forms of synaptic plasticity such as long-term potentiation and depression, phenomena that may underlie physiological processes such as learning and memory. Due to their voltage dependence and calcium permeability, NMDA receptors play a key role in the initiation of synaptic plasticity and the expression of these phenomena are due to alterations in the cell surface expression of AMPA receptors. The role of kainate receptors is less clear, but in the hippocampus and spinal cord, there is evidence for a presynaptic location and an influence on transmitter release. The evidence that NMDA receptors are involved in neurodegenerative processes led to numerous unsuccessful clinical trials in stroke and head trauma with drugs that antagonize the receptor through binding to the glutamate, glycine and allosteric sites. AMPA receptor antagonists also have neuroprotective and anticonvulsant properties in animal studies. Memantine, which is a low affinity NMDA receptor channel blocker has shown cognitive improvements in Alzheimer's patients. NMDA receptor antagonists have also shown beneficial effects to alleviate the motor dysfunction in Parkinson' s disease and relieve pain in animal models. The beneficial effects of AMPAkines in animal models of cognitive impairment and psychosis have prompted clinical studies in these areas. Kainate receptor antagonists have shown positive effects in animal and human models of pain and migraine.

The Tables below contains accepted modulators and additional information. For a list of additional products, see the Materials section below.

Table 1.

Currently Accepted Name	Glutamate site	NMDA Glycine site	Other
Alternate Name			Quisqualate
Structural Information	NR1 (920 aa human) NR2A (1464 aa human) NR2B (1484 aa human) NR2C (1233 aa human) NR2D (1329 aa rat) NR3A (1115 aa rat) NR3B (1003 aa mouse)	Not Known	Not Known
Subtype Selective Agonists	N-Methyl-D-aspartic acid (M3262) Quinolinic acid (P63204)	Glycine (G7126) D-Serine (S4250) R(+)-HA-966 (H130) (partial)	Cyclothiazided (C9847) LY503430d
Subtype Selective Antagonists	D(–)-AP-5 (A8054) D(–)-AP-7 CGS19755 CGP37849 (SML0050) LY382884 (GluR5) (±)-CPP (C104) D-CPP D-CPPene EAA-090 (SML0206)	7-Chlorokynurenic acid 5,7-Dichlorokynurenic acid (D138) MNQX L-689,560 L-701,324 (L0258) GV 150526	Ro 25-6981 (R7150) (NR2B) Ro 8-4304 (R8900) (NR2B) CP 101,606 (SML0053) (NR2B) Ifenprodil (I2892) (NR2B) SPD-502
Channel Blockers	MK-801 (Dizocilpine) (M107) Phencyclidine (PCP) (P3029) CNS-1102 (Cerestat) (C4238) Ketamine (K2753) Memantine (M9292)	Not Known	Not Known
Channel Permeability	Intrinsic ion channel (Na+/K+/Ca2+)	Not Known	Not Known
Radioligands of Choice	[3H]-CPP [3H]-L-Glutamate	[3H]-5,7-Dichlorokynurenate [3H]-L-689,560	[3H]-MK-801 (channel) [3H]-Ro 25-6981 (NR2B)
Tissue Expression		Receptors are widespread in the CNS
Physiological Function	Each class of receptors is involved in fast synaptic transmission, and neuronal plasticity in the developing and adult CNS; Kainate receptors have presynaptic role
Disease Relevance		Stroke, Alzheimer's disease, Parkinson's disease, schizophrenia, pain, epilepsy

Table 2.

Currently Accepted Name	AMPA	Kainate
Alternate Name
Structural Information	iGluR1 (889 aa human) iGluR2 (883 aa human) iGluR3 (894 aa human) iGluR4 (881 aa rat)	iGluR5 (978 aa human) iGluR6 (877 aa rat) iGluR7 (919 aa human) KA1 (956 aa human) KA2 (962 aa human)
Subtype Selective Agonists	AMPA (A0326) S(–€“)-5-Fluorowillardiine CX-614d Cyclothiazided (C9847) LY503430d	Kainic acid (K0250) Domoic acid (D6152) 4-Methylglutamate (G137)
Subtype Selective Antagonists	NBQX (N183) GYKI 52466c (G119) GYKI 53655c (G7798) CNQX (C239) DNQX (D0540) YM90K LY294486 Ro 48-8587 SPD-502	CNQX (C239) DNQX (D0540) NS 102b (N179) LY293558 (iGluR5) NS3763 (N1162) (iGluR5)
Channel Blockers	Joro Spider Toxin	Not Known
Channel Permeability	Intrinsic ion channel (Na+/K+/Ca2+)	Intrinsic ion channel (Na+/K+/Ca2+)
Radioligands of Choice	[3H]-AMPA [3H]-Ro 48-8587	[3H]-Kainic acid [3H]-NBQX
Tissue Expression	Receptors are widespread in the CNS	Receptors are more discretely localized in areas of cortex, hippocampus, thalamus and spinal cord
Physiological Function	Each class of receptors is involved in fast synaptic transmission, and neuronal plasticity in the developing and adult CNS; Kainate receptors have presynaptic role
Disease Relevance	Epilepsy, stroke, Alzheimer'€™s disease, schizophrenia	Pain, epilepsy

Footnotes

a) Ion channel family is also referred to as ionotropic.

b) Selectively inhibits low affinity [3H]-kainate binding.

c) Non-competitive antagonist.

d) Allosteric potentiator.

Abbreviations

AMPA: α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid
AP-5: 2-Amino-5-phosphonopentanoic acid
AP-7: 2-Amino-7-phosphonoheptanoic acid
ATPA: (RS)-2-Amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid
D-CCPene: D-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonene
CGP37849: D,L-(E)-2-Amino-4-methylphosphono-3-pentanoic acid
CGS19755: 4-Phosphonomethyl-2-piperidinecarboxylic acid (Selfotel)
CNQX: 6-Cyano-7-nitroquinoxaline-2,3-dione
CNS 1102: N-(1-Naphthyl)-N'-(3-ethylphenyl)-N'-methyl-guaniaine HCl
CP 101,606: (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol
CPP: 3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid
CX-614: 2H,3H,6aH-Pyrolidino[2",1"-3' ,2' ]1,3-oxazino[6' ,5' ,-5,4]benzo[e]1,4-dioxan-10-one
DNQX: 6,7-Dinitroquinoxaline-2,3-dione
EAA-090: [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid
GV 150526: 3-[2-(Phenylamino)carbonyl]ethenyl-4,6-dichloroindole-2-carboxylic acid
GYKI 52466: 1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
GYKI 53655: 1-(4-Aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine
HA-966: 1-Hydroxy-3-aminopyrrolid-2-one
L-689,560: (±)-4-(trans)-2-Carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline
L-701,324: 7-Chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)-quinolinone
LY293558: (3S,-4aR,6R,8aR)-6-[2-([1Htetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid
LY382884: 3S,4aR,6S,8aR-6-((4-Carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
LY503430: (R)-4' -[1-Fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide
MNQX: 5,7-Dinitro-1,4-dihydro-2,3-quinoxalinedione
NBQX: 2,3-Dihydro-6-nitro-7-sulphamoyl-benzo(f)quinoxaline
NMDA: N-Methyl-D-aspartic acid
NS 102: 5-Nitro-6,7,8,9-tetrahydrobenzo[G]indole-2,3-dione-3-oxime
NS3763: 5-Carboxyl-2,4-dibenzamido-benzoic acid
Ro 25-6981: R-(R*,S*)-α-(4-Hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol
Ro 8-4304: 4-{3-[4-(4-Fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxy-propoxy}-benzamide
Ro 48-8587: 9-(1H-Imidazol-1-yl)-8-nitro-[1,2,4]triazolo[1,5-c]quinazoline-2,5(3H,6H)-dione
SPD-502: 8-Methyl-5(4-(N,N-dimethylsulfamoyl)phenyl)6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyrate-2-yl)oxime
YM90K: 6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione

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