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Questions To Answer:: Effects On The Brain
Questions To Answer:: Effects On The Brain
Questions To Answer:: Effects On The Brain
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
L-Glutamate
L-Aspartate
Excitation
Excitation
Ionotropic; Metabotropic
Ionotropic
?
?
Epinephrine Substance P #
? Excitation
Propanolol, phentolamine ?
Important building block in synthesis of proteins and peptides (ex. Glutathione) Precursor for GABA
? ? Metabotropic (cAMP)*
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
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)
(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 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.
NMDA receptors
Coincidence detectors Cause Long Term Potentiation (LTP) Cause Long Term Depression (LTD)
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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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)
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
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>