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Glutamate Receptors Proteins

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Glutamate Receptors Proteins

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Glutamate Receptors Proteins Background

What is Glutamate Receptor Protein

Glutamate receptors are synaptic and non-synaptic receptors located mainly on the membranes of neuronal and glial cells. They mediate the excitatory synaptic transmission in the brain and spinal cord. According to pharmacology, glutamate receptors could be classified into two main types: metabotropic and ionotropic. They both have effect on synaptic plasticity. Ionotropic glutamate receptors (iGluRs) form the ion channel pore which will be activated when glutamate binds to the receptor. Ionotropic receptors are divided into N-methyl-D-aspartate (NMDA) and non-NMDA receptors. The non-NMDA receptors are AMPA named after a preferred agonist, 4-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptors. Metabotropic glutamate receptors (mGluRs) affect the cell through a signal transduction cascade. Metabotropic glutamate receptors are all named mGluR# and are further classified into three groups according to sequence homology, G-protein coupling, and ligand selectivity, Group 1 includes mGluR1 and mGluR5, Group 2 includes mGluR2 and mGluR3, and Group 3 includes mGluR4, mGluR6, mGluR7, and mGluR8 each group has different functions.

Structure of Ionotropic Glutamate Receptors

Structural studies on iGluRs including AMPA receptors (AMPARs), kainate receptors, and NMDA receptors (NMDARs) showed that iGluRs contain four domains: the extracellular amino-terminal domain (ATD), the extracellular ligand-binding domain (LBD), four transmembrane domains (TMD), and an intracellular carboxyl-terminal domain (CTD). They assemble into tetramers within respective subclasses to form ligand-gated ion channels. (Figure 1)

Structure of Ionotropic Glutamate Receptors. (A) The ionotropic glutamate receptor subunits are composed of the amino-terminal domain (ATD), ligand-binding domain (LBD), transmembrane domain (TMD), and the carboxy-terminal domain (CTD). The TMD is composed of M1–M4 helices. (B) non-NMDARs. (C) NMDARs, The four subunits (A–D) in non-NMDARs. Figure 1. Structure of Ionotropic Glutamate Receptors. (A) The ionotropic glutamate receptor subunits are composed of the amino-terminal domain (ATD), ligand-binding domain (LBD), transmembrane domain (TMD), and the carboxy-terminal domain (CTD). The TMD is composed of M1–M4 helices. (B) non-NMDARs. (C) NMDARs, The four subunits (A–D) in non-NMDARs.

Function of Ionotropic Glutamate Receptors

iGluRs are important for the development and function of the nervous system. They are crucial in memory and learning, and related to many diseases like Alzheimer, Parkinson and Huntington diseases, schizophrenia, epilepsy Rasmussen encephalitis and stroke. iGluRs are found throughout the brain including cortical regions, hippocampus, amygdala, basal ganglia, midbrain, hindbrain, and brainstem nuclei. iGluRs allow ions like Na+, K+ or Ca2+ to pass through the channel upon binding with glutamate. An action potential (AP) can be generated after the activation of iGluRs. When this signal is received, Glutamate removed from the synaptic cleft by excitatory amino acid transporters (EAATs), and turn off the signal in preparation for subsequent APs. This will produce excitatory postsynaptic current, but the speed and duration of the current is different various from each type. NMDA receptors have a binding site for Mg2+ ion, which create a voltage-dependent block. Since the block could only be removed by the outward flow of positive current. Therefore, NMDA receptors rely on the excitatory postsynaptic current produced by AMPA receptors to open. NMDA receptors are permeable to Ca2+. The flow of Ca2+ through NMDA receptors cause both long-term potentiation (LTP, of synapse efficacy) and long-term depression (LTD) by transducing signaling cascades and regulating gene expression.

Structure of Metabotropic Glutamate Receptors

The metabotropic glutamate receptors (mGluRs) are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. mGluRs participate in the modulation of synaptic transmission and neuronal excitability in the central nervous system. GPCRs are membrane-bound proteins that are activated by extracellular factors such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins.

mGluRs contain four domains. (1) A large extracellular N-terminal domain: Venus flytrap domain (VFD), which contains the glutamate-binding site. (2) Cysteinerich domains (CRDs), which contains nine critical cysteine residues, eight of them are linked by disulfide bridges. (3) Heptahelical Domain and Intracellular Loops. (4) C-Terminus. In general, VFDs bind glutamate and other orthosteric ligands. The cysteine-rich domain links the VFDs to seven transmembrane-spanning domains. The C-terminus is subject to alternative splicing to generate different C-terminal protein tails. The open-open state is the inactive state and can be stabilized by antagonists. One or two VFDs can bind glutamate, then the active receptor conformations formed. (Figure 2). 

mGluR dimer in different activity states. Figure 2. mGluR dimer in different activity states.

Function of mGluRs

Generally, group 1 mGluRs are located in postsynaptic locations. Group 2 and group 3 receptors are localized in presynaptic locations. In presynaptic locations, mGluR2, mGluR3, mGluR4, and mGluR8 are generally found in extrasynaptic locations, and mGluR7 primarily located in the active zone. Group 2 and 3 receptors inhibit the release of glutamate or GABA, and group 1 receptors promote release when occur. The glutamate gated ion channels NMDA, AMPA and kainate respond to glutamate with increases in intracellular Na+ or Ca2+, and promote cell excitability at the postsynaptic terminal. Group 1 mGluRs signal via Gq proteins to increase intracellular calcium. In addition, mGluR5 and NMDA receptors are closely linked reciprocally regulated by phosphorylation. Postsynaptic mGluR2/3 and GABAB1/2 receptors couple to cAMP inhibition. GABAA chloride channels modulate intracellular chloride. Expression of mGluR3 and mGluR5 on glia is another key site for mGluR regulation of synaptic activity.

References

  1. Karakas E, Regan M C, Furukawa H. Emerging structural insights into the function of ionotropic glutamate receptors[J]. Trends in Biochemical Sciences, 2015, 40(6):328-337.
  2. Niswender C M, Conn P J. Metabotropic glutamate receptors: physiology, pharmacology, and disease[J]. Annual Review of Pharmacology and Toxicology, 2010, 50(1):295-322.
  3. Krieger J, Bahar I, Greger I. Structure, dynamics, and allosteric potential of ionotropic glutamate receptor N-terminal domains[J]. Biophysical Journal, 2015, 109(6):1136-1148.

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