3. Excitatory Amino Acid Neurotransmitters

Excitatory amino acid neurotransmitters examples (3)

Glutamate, aspartate, homocysteic acid

what do excitatory amino acid neurotransmitters do

Produce an excitatory response in neurons

• i.e., the neuron is more likely to send an action potential

Most important NT for normal brain function

Glutamate (Nearly all excitatory neurons in CNS are glutamatergic)(but remember glutamate is present in all cells!)

Glutamate is synthesised from ______ by what enzyme

Glutamate is synthesised from glutamine by glutaminase

Glutamate that has been released is taken up by what

astrocytes

When glutamate is taken up by astrocytes, it is converted to what by what enzyme

it is converted back to glutamine by glutamine synthetase

Antagonists of the NMDA receptor

D-AP5

MK801

Mg²⁺

Significance of AMPA receptors & NMDA receptors being on the same membrane generally

The opening of NMDA receptor is reliant on the AMPA receptor

How is the NMDA receptor reliant on the AMPA receptor

How many classes & subtypes of Metabotropic Glu receptors are there

3 classes: at least 8 subtypes, mGluR1-8

On what part of the synapse do metabotropic Glu Groups 1-3 act

Group I mainly postsynaptic

Group II and III - mainly presynaptic

Metabotropic Glu Group 1 is linked to the activation/inhibition of what

activation of phospholipase C

Metabotropic Glu Group 2 & 3 are linked to the activation/inhibition of what

Linked to inhibition of adenylate cyclase

What Metabotropic Glu receptor subtypes fall under what groups

Metabotropic Glu receptors may also play a role in memory formation - how?

NMDA receptor activation potentiates signalling via mGluRs

mGluR inhibitors block memory formation at some synapses

Link between excitatory amino acid receptors & stroke

It is usually excitatory amino acid receptors that cause the damage associated with strokes

How do excitatory amino acid receptors cause the damage associated with strokes

With the ischemia that comes with the block in blood supply, there is excessive Glu release → causes over-stimulation of NMDA receptors → Excess Ca2+ influx into postsynaptic neurons → Leading to excitotoxic cell death (excitotoxicity)

Explain how the bold part works: With the ischemia that comes with the block in blood supply, there is excessive Glu release → causes over-stimulation of NMDA receptors → Excess Ca2+ influx into postsynaptic neurons → Leading to excitotoxic cell death (excitotoxicity)

Large influx of Ca2+…

• Can activate proteases (calpains), phospholipases, nitric oxide synthase (NOS), nucleases etc. → Leads to very rapid cell death by necrosis

• Is spotted & gathered into mitochondria resulting in swelling and eventual rupture of mitochondria → Leads to delayed cell death

NMDA-R antagonists; _____ and _____ provide protection in models of ischemia

NMDA-R antagonists D-AP5 and MK801 provide protection in models of ischemia

Take a moment to compartmentalise :)

Give an example of an inhibitory amino acid neurotransmitter

GABA

What do inhibitory amino acid neurotransmitters do

They cause an influx of negatively charged ions such as Cl-

Inside of cell becomes more negative

Hyperpolarisation of post-synaptic cell making it less likely to initiate an action potential

What is the main inhibitory NT in the brain

γ-aminobutyric acid (GABA)

Approx ___% of synapses in brain uses GABA

Approx 33% of synapses in brain uses GABA

Presence of ____ indicates a GABAergic neuron

Presence of GAD indicates a GABAergic neuron

From which amino acid is GABA synthesized

Glutamate.

Which enzyme converts glutamate into GABA

With which cofactor does it do this?

Glutamic acid decarboxylase (GAD), with pyridoxal phosphate as a cofactor.

Which transporter loads GABA into synaptic vesicles?

VIAAT (Vesicular Inhibitory Amino Acid Transporter).

What happens to GABA when the presynaptic terminal is depolarized?

GABA-filled vesicles fuse with the membrane and release GABA into the synaptic cleft.

Which transporter clears GABA from the synaptic cleft?

GAT (GABA transporter).

Where is GABA taken after reuptake?

Into presynaptic neurons or glial cells.

True/False GABA receptors can be Ionotropic & Metabotropic

True

Ionotropic: GABA_A and GABA_C

Metabotropic: GABA_B

The GABA_A​ receptor is structurally related to which receptor?

The nicotinic acetylcholine receptor (nAChR).

Which ion does the GABA_A receptor channel selectively allow through?

Chloride (Cl⁻) ions.

How is the action of GABA at the GABA_A receptor terminated?

GABA is removed from the synaptic cleft by GABA transporters (GAT).

Effect of Benzodiazepines on the GABA_A receptor

They increase the frequency of Cl⁻ channel opening when GABA is present → Increased hyperpolarisation → increased relaxant

Effect of Barbiturates on the GABA_A receptor

They increase the duration of Cl⁻ channel opening when GABA binds.

Can directly activate the receptor even without GABA

Increase hyperpolarisation

How does Presynaptic inhibition work

Inhibitory NT binds to receptors on the presynaptic cell → 

Reduction in depolarisation of the presynaptic nerve terminal → Less Ca2+ influx → Less excitatory NT release

Grey: fill in blank

Green: Fast/Slow

Yellow: Give 4 examples

What are Biogenic amines

Bioactive amine neurotransmitters

What do Biogenic amines do

Implicated in wide range of behaviours

E.g., movement, reward, addiction, depression, sleep

What do Biogenic amines all have in common

Catecholamines structure

What catecholaminergic neuron is for the NT dopamine

Dopaminergic neurons

What catecholaminergic neuron is for the NT norepinephrine

Adrenergic neurons

What catecholaminergic neuron is for the NT epinephrine

Adrenergic neurons

catecholamine neurotransmitters are all derived from what

They are all derived from tyrosine

Explain the pathway from tyrosine to catecholamine neurotransmitters such as epinephrine

(no enzymes - just intermediates)

Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine

The rate limiting step in the formation of catecholamine neurotransmitters is controlled by what enzyme

Tyrosine hydroxylase

Where is Tyrosine hydroxylase found

Only found in sympathetic neurons and adrenal chromaffin cells

If a cell has tyrosine hydroxylase, it is known as a what

catecholaminergic cell

Which transporter loads monoamines into synaptic vesicles?

Vesicular monoamine transporter (VMAT).

Which neurotransmitter classes does VMAT transport?

Catecholamines (dopamine, norepinephrine, epinephrine) and indoleamines (e.g., serotonin).

What drug inhibits VMAT?

Reserpine.

Which enzyme is found inside vesicles of adrenergic neurons?

Dopamine β-hydroxylase (DBH).

What is the function of dopamine β-hydroxylase?

It converts dopamine into norepinephrine inside vesicles.

What are the vesicles in adrenal chromaffin cells called?

Chromaffin granules.

True/False Dopamine receptors, D1, D2 &D5 only are coupled to G proteins

False: Dopamine receptors, D1-D5 are all coupled to G proteins

There are 2 types of dopamine receptors D1-like receptors and D2-like receptors. What receptors (1-5) are in each of these groups & what do they do?

D1-like receptor: D1 and D5 – activate adenylate cyclase (increases cAMP)

D2-like receptor: D2,3,4 – inhibit adenylate cyclase (decreases cAMP)

What is the main mechanism for inactivation of dopamine and other biogenic amines

Reuptake into presynaptic terminals or glial cells.

Which transporter is responsible for dopamine reuptake?

Na+-dependent DA (dopamine) transport protein

Which drugs inhibit dopamine reuptake via DAT (dopamine transporter)

Cocaine and amphetamines

Besides reuptake, how else can biogenic amines be inactivated?

By enzymatic degradation.

Minor way: Diffusion out of the synaptic cleft.

Which enzymes degrade dopamine

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

How does MAO: Monoamine oxidase degrade dopamine

MAO enzymes deaminate catecholamines → inactive derivatives

Where does MAO: Monoamine oxidase degrade dopamine

Associated with outer mitochondrial membrane

How does COMT: Catechol-O-methyltransferase degrade dopamine

Transfers methyl groups to hydroxyl group of catechols

Where does COMT: Catechol-O-methyltransferase degrade dopamine

Cytosol

Which enzyme MAO: Monoamine oxidase / COMT: Catechol-O-methyltransferase works with AD (aldehyde dehydrogenase)

MAO: Monoamine oxidase

What diseases is dopamine associated with

• Parkinson's disease

• Attention deficit hyperactivity disorder

• Tourette syndrome

• Schizophrenia

• Bipolar disorder

• Addiction

What is Parkinson’s disease

Insufficient dopamine in the nigrostriatal pathway

Dopaminergic neurons project from where to where

Dopaminergic neurons project from the substantia nigra to the striatum

Which one has Parkinson’s disease? Explain

How does loss of dopamine cause impairment of motor control

Causes of Parkinson’s disease

How would you know that the second 2 pictures have Parkinson’s disease

Loss of pigmented neurons

Presence of Lewy bodies

What are some treatments for Parkinson’s disease

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