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Questions to Answer:
(1) How do the following neurotransmitters affect synaptic or junctional transmission ? Do they exert excitatory or inhibitory effects ? both ?

Glutamate
Effects on the brain

Table 13-1 Known and Putative Transmitter Substances in the Mammalian Nervous System Substance Acetylcholine Presumed action Excitation, Inhibition Inhibition Inhibition Excitation, inhibition Excitation, inhibition Excitation, inhibition Locations of maximum concentration Interpeduncular, dorsal raphe and caudate nuclei, nucleus accumbens, ventral horn of spinal cord Spinal cord, medulla, pons Cerebellum, cerebral cortex, spinal cord, retina Pons, medulla Putamen, caudate, locus ceruleus, hypothalamus Amygdala, hypothalamus, septum, striatum Mode of action Ionotropic, Metabotropic (cGMP)* Ionotropic Ionotropic Metabotropic (cAMP)* Metabotropic (cAMP)* ? Blocking agents Curare, atropine

Significance
Major Excitatory Neurotransmitter
Most excitatory neurons in the CNS are glutaminergic Half of CNS neurons utilize it

Glycine gamma-aminobutyric acid Norepinephrine Dopamine Serotonin (5-HT)

Strychnine Bicuculline Propanolol, phentolamine Phenoxybenzamine LSD

Critical Role in Synaptic Plasticity

Learning memory

L-Glutamate
L-Aspartate

Excitation
Excitation

Temporal cortex, basal ganglia, cerebellum, amygdala

Substantia nigra, occipital cortex, thalamus, cerebellum, hypothalamus Thalamus, hypothalamus Substantia nigra, trigeminal nucleus, dorsal horn of spinal cord, limbic system Globus pallidus, caudate, nucleus accumbens, hypothalamus Pituitary, striatum, spinal cord Hypothalamus, thalamus

Ionotropic; Metabotropic
Ionotropic

?
?

Epinephrine Substance P #

? Excitation

Metabotropic (cAMP)* Metabotropic (?)

Propanolol, phentolamine ?

Important building block in synthesis of proteins and peptides (ex. Glutathione) Precursor for GABA

Enkephalins# Endorphins# Histamine

Inhibition Inhibition Inhibition

? ? Metabotropic (cAMP)*

Naloxone Naloxone Ethanolamine, butamide

Others: Taurine, neurotensin, carnosine, angiotensin II, hypothalamic releasing factors, serine, proline, N-acetyl-L-aspartate, adenosine, P-tyramine, tryptamine Peptides cAMP = cyclic adenosine monophospate cGMP = cyclic guanine monophosphate LSD = lysergic acid diethylamide

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Synthesis
Three theories on glutamate synthesis according to compartmentation studies:
From glutamine via phosphate activated glutaminase
Regulated by negative feed back

From 2-oxoglutamate and aspartate via aspartate aminotransferase

Glucose becomes 2-oxoglutamate via citric acid cycle or pyruvate carboxylase
Uptake via astrocyte or nerve terminal

From 2-oxoglutamate via -aminotrasnferase

Synaptic Packaging and Release

Ca++ dependent release 1. Packaged into synaptic vesicles by VGLUT 2. Depolarization via action potential 3. Ca++ influx 4. Vesicle Migration to and fusion with axonal membrane 5. Release into synaptic cleft

Reuptake and Recycling

Via Excitatory Amino acid transporters (EAAT)
Na++ dependent

Returns to pre-synaptic terminal or glial cells Converted into glutamine by glial cells Glial cells return glutamine to pre-synaptic neuron to be recycled into glutamate

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Antagonists
Phenocyclidine
Angel dust Hallucinogenic drug Blocks open receptor channels

Ketamine
Anesthesia Can attenuate neuronal damage caused by anoxia

Clinical Correlations
Excitotoxicity due to excessive release of Glutamate into the synaptic cleft Glutamate signalling plays a pivotal role in many physiological functions including learning and remembering. However, it is also a potent neurotoxin and is increasingly being implicated in the pathogenesis of neurological diseases including stroke, head trauma, epilepsy, AIDs, Huntingtons, Parkinsons and Alzheimers disease

Neuronal development
By facilitating Ca++ Differentiation Survival Migration Blockage of Glutaminergic receptors during prenatal period cause apoptosis to susceptible neurons

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Neurodegeneration
1. exogenous glutamate consumed through the diet
Domoate poisoning

Effect of Alcohol
Ethanol inhibits Ca++ channel of NMDA receptors
NMDA receptors implicated in cognitive function black outs due to inhibition of receptor NMDA activity

2. endogenous glutamate released from neurons can contribute to damage from ischemia or traumatic brain injury 3. activation of glutaminergic receptors leads to apoptosis in neurodegenerative diseases (ALS, Alzheimers, Huntingtons, Parkinsons)

Alcohol withdrawal syndrome may cause seizures

Due to upregulation of the long suppressed NMDA receptors

Pain Perception and Itching

Mechanical pain, heat pain, capsaicin-evoked pain, inflammatory pain, and neuropathic pain is related to glutaminergic receptors Suppression of itching is also related to glutaminergic receptors

(2) Describe their receptors and their postsynaptic signalling mechanisms . Are they ionotropic or G-proteincoupled metabotropic receptors, or both ? What changes do they effect in the postsynaptic cells ?

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Glutamate: Transmitter-Receptor Interactions

L-Glutamate is the major excitatory neurotransmitter

Glutamate Receptors
Ligand gated/Ionotropic Kainate (KA) -amino-3-hydroxy-5methylisoxazole-4-propionate (AMA) N-methyl-D-aspartate (NMDA) Metabotropic mGluR Indirect ion channel via G-protein May cause slow post synaptic excitation
Via PLC

in the mammalian CNS. Has two classes of receptors, ligand gated ion channels (ionotropic receptors) and G-protein coupled (metabotropic) receptors. Activation of these receptors is responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), mechanisms that are thought to underlie learning and memory.

Inhibit presynaptic excitation

Via adenylyl cyclase

NMDA receptors
Coincidence detectors Cause Long Term Potentiation (LTP) Cause Long Term Depression (LTD)

Ionotropic Glutamate Receptors

Structure of the ionotropic glutamate receptors

General structure of an ionotropic glutamate receptor subunit. The large N-terminal domain is extracellular while the shorter C-terminal domain is intracellular.

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Ionotropic Glutamate Receptors

Upon binding, the agonist will stimulate direct action of the

Two iGluR types have been identified: (1) NMDA receptors (2) non-NMDA receptors NMDA receptors. Glutamate binding onto an NMDA

central pore of the receptor, an ion channel, allowing ion flow and causing an excitatory post synaptic current. This current is depolarizing, and if enough glutamate receptors are activated, will trigger an action potential in the postsynaptic neuron. Glutamate binding onto an ionotropic receptor directly influences ion channel activity because the receptor and the ion channel form one complex These receptors mediate fast synaptic transmission between neurons

receptor also opens non-selective cation channels, resulting in a conductance increase. However, the high conductance channel associated with these receptors is more permeable to Ca+2 than Na+ ions Non-NMDA receptors Glutamate binding onto a non-NMDA receptor opens nonselective cation channels more permeable to sodium (Na+) and potassium (K+) ions than calcium (Ca+2)

Metabotropic glutamate receptors

Unlike ionotropic receptors, which are directly linked to an APB receptor. In contrast to non-NMDA and NMDA

ion channel, metabotropic receptors are coupled to their associated ion channel through a second messenger pathway. Ligand (glutamate) binding activates a G-protein and initiates an intracellular cascade.

receptors, glutamate binding onto an APB receptor elicits a conductance decrease due to the closure of cGMPgated non-selective cation channels

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Citation
Brunton, Laurence, John Lazo, Keith Parker. Goodman and Gilman's The

Pharmacological Basis of Therapeutics. New York: Mc Graw Hill, 2009.

Katzung, Bertram. Basic and Clinical Pharmacology. San Francisco : Mc

Grawhill, 2007.
Frod, Fonnum. "Glutamate: A neurotransmitter in Mammalian

Brain." Journal of Neurochemistry 42.1. (1984): 1-11. Web. 8 Feb. 2012. http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.1984.tb09689.x/pdf
Meldrum, Brian S. "Glutamate as a Neurotransmitter in the Brain: Review

THANK YOU ;]

of Physiology and Pathology." Journal of Nutrition 130.4. (2000): 10071015. Web. 8 Feb. 2012. http://jn.nutrition.org/content/130/4/1007.short
Liu, Yang, et al. "VGLUT2-Dependent Glutamate Release from

Nociceptors Is Required to Sense Pain and Suppress Itch." Cell Press 68. (2010): 543-556. Web. 8 Feb. 2012. <http://pdn.sciencedirect.com/science?_ob=MiamiImageURL&_cid=2721 95&_user=10&_pii=S0896627310007257&_check=y&_coverDate=201011-04&view=c&_gw=y&wchp=dGLbVlVzSkWz&md5=49d7a10961856ad0ae3a97c94f2f5915/1-s2.0S0896627310007257-main.pdf>