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Nomenclature

The two main types of Glutamate Receptors are referred to as Metatropic and Ionotropic. Ionotropic receptors tend to be quicker in relaying information but Metatropic are associated with a more prolonged stimulus. This is due to the usage of many different messengers to carry out the signal but since there is a cascade, just one activation of a G-protein can lead to multiple activations. Glutamate Receptors are usually not specifically geared towards Glutamate exclusively as the ligand and sometimes even requires another agonist.

Structure/Mechanism

Glutamate receptors are transmembrane proteins and exist primarily the central nervous system. These receptors can be found on the dendrites of post-synaptic cells and bind to glutamate released into the synaptic cleft by pre-synaptic cells. The glutamate binds to the extracellular portion of the receptor and provokes a response, however the various types of receptors can produce different responses.[1]

Ionotropic Glutamate Receptors

All ionotropic glutamate receptors are ligand-gated nonselective cation channels which allow the flow of K+, Na+ and sometimes Ca2+ in response to glutamate binding. All produce excitatory post-synaptic current, but the speed and duration of the current is different for each type. NMDA receptors have an internal binding site for an Mg+ ion creating a voltage dependant block which is removed by outward flow of positive current. [2] This causes NMDA receptors to have a slower and more prolonged post-synaptic current than AMPA/kainite receptors.

Metabatropic Glutamate Receptors

Metabatropic glutamate receptors, which belong to the C family of G protein-coupled receptors are divided into three groups, with a total of eight sub-types. The mGluRs are composed of three distinct regions: the extracellular region, the transmembrane region, and the intracellular region. [3] The extracellular region is composed of a Venus Flytrap (or VFT) module that binds glutamate, [4] and a cysteine-rich domain that is thought to play a role in transmitting the conformational change induced by ligand binding from in the VFT module to the transmembrane region. [3] The transmembrane region consists of 7 transmembrane domains and connects the extracellular region to the intracellular region where G protein coupling occurs. [4] Glutamate binding to the extracellular region of an mGluR causes G proteins bound to the intracellular region to be phosphorylated which affect multiple biochemical pathways and ion channels in the cell. [5] Because of this, mGluRs can both increase or decrease the exitability of the post synaptic cell, thereby causing a wide range of physiological effects.

Function/Evolution

Genetics

Pathology

Excitotoxicity

Overstimulation of glutamate receptors causes neuronal degradation and death through a process called excitotoxicity. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors, causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.[6] High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death.[7] Ingestion or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[8]

Neurodegeneration

In the case of traumatic brain injury or cerebral ischemia (e.g. cerebral infarction or hemorrhage), acute neurodegeneration may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure, decreasing ion concentration gradients across the plasma membrane. Depolarization increases synaptic release of glutamate[9] and reversed glutamate transport (efflux) in affected neurons and astrocytes[10]. In addition, neuronal death releases cytoplasmic glutamate outside of the ruptured cell.[10] These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.

Neurogenerative Diseases

Glutamate receptors’ significance in exitotoxicity links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.[11] Neurogenerative diseases thought to be mediated (at least in part) through stimulation of glutamate receptors [12]:

Current Research

Glutamate Receptors have been found to have an influence in ischemia/stroke, seizures, Parkinson's Disease, Huntington's Disease, and aching.[13] As mentioned in the pathology section, almost every disease involving Glutamate Receptors have very similar if not identical pathways, differing slightly only in the area in the brain where the issue occurs.

Ischemia

It has been observed that during ischemia, the brain has an unnaturally high concentration of extracellular glutamate. [14] This is linked to an inadequate supply of ATP which drives the glutamate transport levels that keep the concentrations of glutamate in balance.[15] This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this over exposure, the post synaptic terminals tend to keep glutamate around for long periods of time which result in a difficulty in depolarizing.[15] Antagonists for NDMA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia. [8]

Seizures

There has been some discovery about the role of Glutamate Receptors in epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors help counteract the epileptic symptoms. [16] Since Glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing so applying an antagonist to these receptors helps in preventing convulsions.[17]

Parkinson's Disease

Late onset neurological disorders like Parkinson's disease have partial reliance on endogenous glutamate binding NMDA and AMPA glutamate receptors. [8] Invitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motoneurons which was counteracted by some AMPA receptor antagonists like GYKI 52466.[8] Research also suggests that the metabotropic glutamate receptor, mGlu4, is directly involved in movement disorders associated with the basal ganglia through selectively modulating glutamate in the striatum. [18]

Huntington's Disease

In addition to similar mechanisms causing Parkinson's Disease in respect to NMDA or AMPA receptors, Huntington's disease was also proposed to exhibit metabolic and mitochondrial deficiency which exposes striatal neurons to over activation of the NMDA receptor to dangerous levels.[8] There has been a proposition of using folic acid as a possible treatment for Huntington's due to the inhibition it exhibits on homocysteine which increases vulnerability of nerve cells to glutamate.[19] This could decrease the effect that the glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity.

Aching

Hyperalgesia is directly involved with spinal NMDA receptors. Antagonizing NMDA in a clinical setting produces side effects not fit for mass consumption although more research is being done in intrathecal administration.[8]

Effects Outside the Nervous System

Glutamate receptors are thought to be responsible for the reception and transduction of umami taste stimuli. Taste receptors of the T1R family, belonging to the same class of GPCR as metabotropic Glutamate Receptors are involved. Additionally, the mGluRs as well as ionotropic glutamate receptors in neural cells have been found in taste buds and may contribute to the umami taste. [20]

References

  1. ^ Dingledine R, Borges K, Bowie D, Traynelis SF (1999). "The glutamate receptor ion channels". Pharmacol. Rev. 51 (1): 7–61. PMID 10049997. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Johnson JW and Ascher P (1990) Voltage-dependent block by intracellular Mg2+ of N-methyl-D-aspartate activated channels. Biophys J 57: 1085-1090[Medline]
  3. ^ a b Takanori Muto et al. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors PNAS 2007 104:3759-3764; published online before print February 26, 2007, doi:10.1073/pnas.0611577104
  4. ^ a b J.P. Pin and F. Acher, The metabotropic glutamate receptors: structure, activation mechanism and pharmacology, Current Drug Targets: CNS and Neurological Disorders 1 (2002), pp. 297–317.)
  5. ^ Platt SR (2007). "The role of glutamate in central nervous system health and disease--a review". Vet. J. 173 (2): 278–86. doi:10.1016/j.tvjl.2005.11.007. PMID 16376594.
  6. ^ Dubinsky JM. Intracellular calcium levels during the period of delayed excitotoxicity. J Neurosci. 1993; 13(2): 623–631.
  7. ^ Manev H, Favaron M, Guidotti A, and Costa E. Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Molecular Pharmacoloy. 1989 Jul;36(1):106-112. PMID 2568579.
  8. ^ a b c d e f Meldrum, B. (1993) Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders. Brain Res. Rev. 18: 293–314. Cite error: The named reference "mel1" was defined multiple times with different content (see the help page).
  9. ^ Hirsch JA, Gibson GE. Selective alteration of neurotransmitter release by low oxygen in vitro. Neurochem Res. 1984; 9(8): 1039–1049.
  10. ^ a b Szatkowski M, Attwell D. Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci. 1994; 17(9): 359–365. Cite error: The named reference "obr1" was defined multiple times with different content (see the help page).
  11. ^ RT Journal A1 Beal, MF T1 Mechanisms of excitotoxicity in neurologic diseases JF The FASEB Journal JO FASEB J. YR 1992 FD December 1 VO 6 IS 15 SP 3338 OP 3344 UL http://www.fasebj.org/cgi/content/abstract/6/15/3338
  12. ^ Budd, S. L., Gillessen, T., & Lipton, S. A. (2008).
    Excitatory amino acid neurotoxicity. Madame Curie Bioscience Database, 2008
  13. ^ "Glutamate Receptors (Glutamate Receptor)." Chi Precision Medical Data Mining. Carehunter Inc. <http://www.curehunter.com/public/keywordSummaryD017470.do.> Web. 24 Oct. 2009.
  14. ^ Nishizawa Y. (2001). "Glutamate release and neuronal damage in ischemia". Life Sci. 69 (4): 369–81. PMID 11459428.
  15. ^ a b Ole Petter Otterson. "Sources of Glutamate in Cerebral Ischemia." The Neurodegeneration Research Group. <http://www.med.uio.no/imb/anatomi/gruppe_3/ischemia.htm> Web. Accessed 25 Oct. 2009.
  16. ^ Astrid G. Chapman (2000). "Glutamate and Epilepsy". Journal of Nutrition: 1043S–1045S.
  17. ^ Moldrich Rx; et al. (2003). "Glutamate metabotropic receptors as targets for drug therapy in epilepsy". Eur J Pharmacol. 476 (1–2): 3–16. PMID 12969743. {{cite journal}}: Explicit use of et al. in: |author= (help)
  18. ^ Cuomo D.; et al. (2009). "Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment". J Neurochem. 109 (4): 1096–105. PMID 19519781. {{cite journal}}: Explicit use of et al. in: |author= (help)
  19. ^ Aline McKenzie. "Test reveals effectiveness of potential Huntington's disease drugs." Innovations Report. <http://www.innovations-report.com/html/reports/life_sciences/report-73183.html> Web. Accessed 25 Oct. 2009.
  20. ^ Kinnamon SC, Vandenbeuch A. Receptors and transduction of umami taste stimuli. Ann N Y Acad Sci. 2009 Jul;1170:55-9. Review. PMID:19686108 <http://www.ncbi.nlm.nih.gov/pubmed/19686108?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum>

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