Excitatory And Inhibitory AAs Flashcards by Amy Hannaford

What are the main inhibitory NTs:

a) in the brain
b) in the spinal cord

a) GABA

b) glycine

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What are the two main excitatory NTs?

Glutamate and aspartate

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Glut, aspartate, GABA and glycine are NON-ESSENTIAL AAs. What does this mean?

They are synthesized in the body not required in diet

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Describe the glycolysis/oxidative metabolism of glucose pathway of synthesising excitatory AAs (glut)

Glucose converted to pyruvate in glycolysis
Pyruvate is decarboxylated to form acetyl-CoA
Acetyl-CoA enters the Krebs cycle
a-ketoglutarate is produced in cycle, undergoes transamination by aminotransferases to form glutamate

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What is the preferred pathway in synthesis of glutamate?

Glutaminase catalyses glutamine –> glutamate

glutaminase undergoes product inhibition

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What are the 3 paths of glutamate breakdown?

Glutamine synthetase - converts glutamate to Glutamine in glia
reversal of transamination - glutamate -> a-ketoglutarate
Glutamate dehydrogenase - glutamate -> a-ketoglutarate

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How are EAAs stored?

In vesicles:
Highly specific transporter for L-glutamate
Proton antiporter system - actively moves H+ in, electrochem grad, transporter moves glut in and H+ out

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Glutamate transporter concentrates glutamate in vesicles until it reaches a concentration of?

50mM

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Describe release and uptake of EAAs (glutamate)

vesicular release and uptake by presynaptic transporters

BUT also release by TRANSPORTER REVERSAL

Transporters have high affinity and low specificity

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How many glutamate transporter subtypes are there?

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Where are glutamate transporters EAAT1-5 each found?

EAAT1 - neurones an astroglia (esp Bergmann glia, cortex, hippocampus and cerebellum)
EAAT2 - astroglia
EAAT3 - neurones
EAAT4 - Cerebellar purkinje cells 
EAAT5 - retina

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Which metabotropic glutamate receptor subtypes are in GROUP I? What do they stimulate?
What compounds are they activated by?

mGluR1 + mGluR5

Gq - stimulate PLC -> IP3 (Ca release)

Activated by trans-ACPD and quisqualate

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Which metabotropic glutamate receptor subtypes are in GROUP II? What do they stimulate?
What compounds are they activated by?

mGluR2 + mGluR3

Gi - inhibit adenylyl cyc

Actuated by trans-ACPD and quisqualate

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Which metabotropic glutamate receptor subtypes are in GROUP III? What do they stimulate?
What compounds are they activated by?

mGluR4, 6, 7, 8

Gi - inhibit adenylyl cyc

Activated by L-AP4 and L-SOP (no effect w trans-ACPD or quisqualate)

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Which group of mGluRs act as autoreceptors?

Group III

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What ions do AMPA, kainate and NMDA allow?

AMPA - Na, K (and some allow Ca)

Kainate - Na, K

NMDA - Na, K, Ca

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Quisqualate is an agonist of which IONOTROPIC receptors?

AMPA and kainate

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What is an agonist of NMDA receptor?

Aspartate

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CNQX is an antagonist of which glutamate receptors?

AMPA

Kainate

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AP5 is an antagonist of which type of glutamate receptor?

NMDA

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How does a conditioning train result in long term potentiation?

= rapid stimulation
Changes efficiency of synapse, makes it stronger
Results in larger responses
Responsible for synaptic plasticity

Train -> sustained depolarization, NMDA block removed
Metabotropic glut receptors activated
AMPA phosphorylation, increased AMPA activity

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How do EEA IONOTROPIC receptors cause stroke, Alzheimer’s and amyotrophic lateral sclerosis?

Sustained activation of AMPA, kainate and esp NMDA receptors
Leads to neuronal cell death due to Ca overload
=> neurodegeneration

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What can provoke overstimulation of EAA receptors and consequently neurodegeneration?

Clue - restriction of blood supply

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Ischemia

What’s the main inhibitory transmitter in:
a) the brain?

b) the spinal cord?

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a) GABA

b) glycine

What is GABA synthesized from? What enzyme catalyses it's synthesis? Where is this enzyme mostly found, what co-factor does it require, and what inhibits it?

Glutamate Glutamate decarboxylase Axon terminals of GABAergic neurones. Pyridoxal phosphate derived from vitB Inhibited by allylglycine.

How is GABA broken down?

Converted in succinic semialdehyde by GABA aminotransferase Succinic semialdehyde converted to succinate by SSADH (succinic semialdehyde dehydrogenase) (Succinate = intermediate in Krebs)

Where is GABA aminotransferase found? What inhibits it? What are it's inhibitors used for?

Mostly in mitochondria (in neurones and Astrocytes) Inhibitors: aminooxyacetic acid and vigabatrin Vigabatrin used to treat epilepsy

Which GABA receptors are IONOTROPIC?

A + C B is metabotropic

Where is GABAc mainly located?

In retina

Why is there huge diversity in GABAa receptors?

6 classes if subunit: a, B, y, d, E, p 19 different polypeptides

What domain of GABAa is thought to line the pore? What controls permeation?

M2 Charged rings

What forms the GABA binding site on GABAa receptor?

Cys (cystine) loop

GABA has 5 distinct binding sites for what molecules? What do agonists of these sites do? (In brackets)

1) GABA 2) benzodiazepine 3) barbiturates (depressants) 4) steroids (anaesthetics) 5) picrotoxin (convulsants)

Why do benzodiazepines and barbiturates decrease anxiety?

Potentiation GABA

What 3 agonists of GABAa?

Muscimol, THIP, isoguvacine

What is a competitive antagonist of GABAa?

Bicuculline

What are non-competitor antagonists of GABAa?

Metrazol (phentylenetrazol) and Picrotoxin (Both bind to picrotoxin site)

How do benzodiazepines and barbiturates affect channel openings of GABAa?

Benzodiazepines: increase FREQUENCY of openings Barbiturates: increase DURATION of openings

What is the most common subunit composition if GABAa (40%)? Where is this isoform located and what are it's properties at these locations?

a1B2y2 Most brain areas, hippocampus - common coassembly Cortical interneurones - BZ type I Cerebellar purkinje cells - Zn insensitive

What subunit is required for GABAa to respond to benzodiazepines?

How does GABAb bring about synaptic inhibition of NT release?

Coupled to Gi, inhibits adenyl cyclase Stimulates PLA2 Activates VG K+ channels Inhibits Ca channels => hyperpolarisation, no NT release

What are agonists of GABAb? What are they used for?

Baclofen, saclofen Muscle relaxants, anti spastic agents

Phaclofen-2-hydroxysaclofen does what to which GABA receptor?

Antagonist of GABAb

What five places are glycine receptors found?

``` Spinal cord grey matter Mindbrain (lower levels) Medulla Thalamus Hypothalamus ``` NB: absent from higher brain levels

What is glycine synthesised from? Using what enzyme?

Serine Serine hydroxymethyltransferase

How is glycine stored?

In vesicles Vesicular transporter hasn't been found, most likely uses GABA transporter

How is glycine taken up from synapse?

Na dependent transporters | Specific (GLYT1, GLYT2)

How many subunits make up a glycine receptor? What classes of subunit? What type of protein are these subunits?

5 a (a1,a2, a3) and B Glycoproteins

How many transmembrane domains make up each subunit if GlyR?

What subunit composition of glycine receptor is found in adults? And in fetus?

Adult: 3a1/2B Fetus: 5a2 (homomer)

What other protein is associated with glycine receptor? Why is it's role?

Gephrin Cytoplasmic protein Binds B subunit to cytoskeleton Responsible for GlyR clustering at inhibitory synapse

What is an allosteric modulator of glycine receptor?

Zinc

Which of the following: B-alanine, cyanotriphenylborate, taurine, strychnine are a) agonists b) antagonists and c) channel blockers of glycine receptor?

a) B-alanine, taurine b) strychnine c) cyanotriphenylborate

How does tetanus toxin affect glycine receptor?

Causes Glycine release | => over activation of muscles

What role do glycine receptors have in whole organism?

Reflex responses- reciprocal and recurrent inhibition Sensory processing Voluntary muscle control

Hyperekplexia (exaggerated reflexes) is caused by mutation of glycine receptors, decreases glycine signalling. How is it treated?

With benzodiazepines (increase GABA activity in SC)

Excitatory And Inhibitory AAs Flashcards

(56 cards)