12_Neuro 1.6 Chemistry Of Neurotransmitters

Front 1

By looking at a neuron, how can you tell it is an excitatory neuron?

Back 1

Bc they are typically asymmetrical.

Front 2

Principle outflow neurons from the brain are predominantly:

Back 2

Glutamatergic

Front 3

Glutamate is synthesized from what?

Back 3

alpha-ketoglutarate

Front 4

Glutamate synthase mediates what rxn? Located where?

Back 4

Glutamate to Glutamine. Glial cells

Front 5

Glutaminase mediates what rxn? Located where?

Back 5

Glutamine to Glutamate. Found in Neurons, Mts.

Front 6

What loads vesicles with glutamate?

Back 6

VGluT - vesicular glutamate transporter.

Front 7

What inhibits the release of Glutamine from the presynapse?

Back 7

Autoreceptors mGluR2 and mGluR3

Front 8

What re-uptakes Glu in presyn and glial cells? What class of transporters are they?

Back 8

Excitatory Amino Acid transporters (EAATs). They are symporters that use Na+

Front 9

What does NMDA conduct?

Back 9

It conducts calcium, sodium, potassium

Front 10

Why is excess Glu toxic to cells? (this is why re-uptake is so important)

Back 10

Bc it activates NMDA causing a rapid rise in Ca++ into the cell. The cell requires a ton of energy to pump it back out.

Front 11

Glu stimulates Ionotropic and Metabotropic Receptors - what are those?

Back 11

Ionotropic R are ligand gated ion channels. Metabotropic R are G protein coupled receptors.

Front 12

What are the two subtypes of Ionotropic receptors? What do they do?

Back 12

1. AMPA
2. Kainate
They both slowly depolarize the cell by allowing primarily Na into the cell.

Front 13

NMDA is a very high conductance channel that is large and allows many different kinds of ions through. However, it primarily conducts Ca - why?

Back 13

Bc Ca has the highest concentration gradient and it is more likely to flow into the cell.

Front 14

In addition to Glu, NMDA receptors require this ligand to open:

Back 14

Glycine

Front 15

What plugs NMDA receptors? What must happen to unplug it?

Back 15

1. Magnesium
2. Depol of the membrane (more pos in the inside)

Front 16

The influx of Ca via NMDA receptors activate what? What do this allow us to do?

Back 16

1. Activates Kinases
2. Learn and form memories

Front 17

Metabotropic receptors are called serpentine receptors bc they cross the membrane ? times. Also, they are coupled with?

Back 17

7 times. G-protein coupled receptors.

Front 18

Where are glutamate receptors typically found?

Back 18

Dendrites

Front 19

AMPA receptors are a subtype of ionotropic Glutamate receptors. What do they conduct? Are they excitatory or inhibitory? Are they fast or slow transmission receptors?

Back 19

Sodium. Excitatory. Fast transmission.

Front 20

What two conditions cause overactive glutamatergic systems? Why?

Back 20

1. Low O2
2. Low glucose
No energy to keep glutamate concentrations low results in hyperexcitability (i.e. seizures)

Front 21

What are two neurological diseases caused by a hyperexcitable glutamateric system. What is one treatment?

Back 21

ALS and Huntington's disease. Inhibition of glutamate

Front 22

Where is the Norepinephrine used? What does it regulate?

Back 22

Brain stem region: Meduula, pons, midbrain. Regulates arousal, autonomic NS system - "wakes you up"

Front 23

Norepi is synthesized in the brain - why must it be made there?

Back 23

Bc it does not cross the blood brain barrier.

Front 24

What is the precursor for norepi?

Back 24

Tyrosine

Front 25

Describe the synthesis of norepi starting from tyrosine.

Back 25

1. Tyrosine Hydroxylase converts Tyrosine --> L-DOPA
2. L-DOPA decarboxylase converts L-DOPA to Dopamine
3. Dopamine Beta Hydroxylase converts Dopamine to Norepinephrine

Front 26

What is lost in Parkinson's? What is used as a treatment?

Back 26

DOPA anergic terminals - i.e. cells that produce DOPA. L-DOPA

Front 27

What is the rate limiting step in norepi synthesis? Note: If Tyrosine is abundant, what is it that is limiting factor?

Back 27

Tyrosine Hydroxylase. BH4 (tetrahydrobiopterin)

Front 28

What regulates BH4 binding to Tyrosine Hydroxylase? How does this mechanism work to regulate the synthesis of norepi?

Back 28

Norepinephrine. It binds to the same site as BH4 so if there is excess NE, then it'll occupy the BH4 and inactive the Tyrosine Hydroxylase. On the other hand, if NE is low, then BH4 will bind and the enzyme is active.

Front 29

Tyrosine Hydroxylase is also regulated via phosphorylation. How?

Back 29

1. Phosphorylation increases the enzyme's affinity for BH4 - activating it.

Front 30

Tyrosine Hydroxylase is also upregulated by Ca2+. Why does this make sense?

Back 30

Bc after an action potential, NE is released and concentration goes down. The AP was stimulated by Ca2+ so its concentration is high. By activating Tyrosine Hydroxylase this way, you get NE synthesis at appropriate times.

Front 31

VMAT2 loads NE vesicles with two compounds:
Why?

Back 31

Loaded with Dopamine and Dopamine beta-hydroxylase. This allows last step to take place which is conversion to NE.

Front 32

What are the three ways that NE can be released?

Back 32

1. Ca- dependent exocytosis
2. Plasma membrane transporters working in reverse (they're leaky)
3. Dendritic release: not calcium dependent.

Front 33

NE has receptors on the presyn that modulate its release. There are two - what are they and how do they modulate?

Back 33

1. Alpha2 receptor inhibits release (decreases Ca sensitivity) (feed back reg)
2. Beta Receptor: Increases release (increased cAMP; more Ca in when channels open) (feedforward reg)

Front 34

What are the three transporters that reuptake NE?

Back 34

NATs, DATs, and SERTs

Front 35

What are the three ways NE is inactivated?

Back 35

1. Reuptake
2. Enzymatic via MAO
3. Inactivation via COMT

Front 36

All 9 NE receptors are this type of receptor:

Back 36

G protein coupled receptors

Front 37

NE receptors include Alpha1, Alpha2 and Beta. What does each one do?

Back 37

1. Alpha1: releases Ca and increases contraction of smooth muscle cells. Induces arousal; stimulation
2. Alpha2: Inhibits adenylyl cyclase thereby inhibiting cAMP
3. Beta: Increases adenylyl cyclase activity and increases cAMP and PKA. Regulates sympathetic and parasympathetic outflow; blood pressure regulation.

Front 38

Where is neurotensin active?

Back 38

Prefrontal cortex; hypothalamus; midbrain

Front 39

What is neurotensin always co-localized with?

Back 39

Dopamine

Front 40

Neurotensin precursor is how big? The final product is how big?

Back 40

1. 170 aa
2. 13 aa

Front 41

The hydrophobic signal sequence of neurotensin directs the protein to what?

Back 41

ER

Front 42

What is neurotensin stored in? They appear dense on EM and are larger or smaller than synaptic vesicles?

Back 42

Secretory vesicles. They are larger than synaptic vesicles.

Front 43

How is neurotensin transported to the axons?

Back 43

Via the secretory pathway

Front 44

Is the concentration of neurotensin high or low at the terminals?

Back 44

Low (and variable)

Front 45

Although release of neurotensin is calcium dependent, it requires this additional features:

Back 45

1. Requires high intensity, rapid firing of neurons

Front 46

Unlike other transmitters, neurotensin can be released: What is the consequence of this?

Back 46

anywhere along the membrane - not just the active zone. It can activate more synaptic neurons besides just the apposing post synaptic neuron.

Front 47

What are the three ways neurotensin is inactivated?

Back 47

1. Extracellular peptidases cleaving the peptide
2. Diffusion away from the synapse
3. No reuptake; but can be internalized of peptide bound to its receptor. Thus it last longer

Front 48

Receptors for neurotensin are:
The fact that it is such a large molecule make is specificity to the receptor

Back 48

G-couple receptors. Specificity is very high

Front 49

2-Arachidonoyglycerol (2-AG) is not an amino acid, not a protein, but a:

Back 49

Lipid

Front 50

Is 2-AG at high or low concentrations in the brain? Where is it found in the brain?

Back 50

1. High
2. Striatum, cerebellum, limbic cortex, hippocampus, amygdala

Front 51

2-AG is the endogenous chemical that binds to the same receptor as:

Back 51

THC - and 2-AG has similar effects on the brain as THC

Front 52

Where is 2-AG stored?

Back 52

It is not stored anywhere - it is synthesized on demand via cascade.

Front 53

What is the precursor for 2-AG? This precursor is converted to what via this enzyme.

Back 53

PIP2 is converted to DAG via Phospholipase C.

Front 54

Once DAG is made, it is converted to what via this enzyme? What is it essentially?

Back 54

DAG is converted to 2-AG via DAG lipase. 2-AG is essentially just the glycerol backbone plus the long chain fatty acid at the SN2 position (usually arachidonic acid)

Front 55

Since PIP2 and IP3 and DAG are ubiquitous, why is 2-AG not synthesized in other locations?

Back 55

Bc only the neurons have DAG Lipase

Front 56

How is 2-AG inactivated?

Back 56

Via Monoacylglycerol Lipase (MGL) that hydrolyzes 2-AG into glycerol and arachodonic acid

Front 57

How does 2-AG leave the the presynapse?

Back 57

Thought through diffusion through membranes.

Front 58

The receptors for 2-AG include cannabinoid. But is also targets G-protein coupled receptors and the receptors are almost always found here:
It inhibits opening of:

Back 58

On the presynaptic nerve! It inhibits Ca gated channels and therefore inhibits neurotransmitter release.

Front 59

Interesting, most 2AG is synthesized and diffuses out of the:

Back 59

Post synaptic neuron. Therefore it is called "Retrograde Neuro transmission"

Front 60

Prof what's us to learn:
1. Mechanisms of synthesis, storage, release and inactivation of the 4NTs
2. Know the names of the important receptors and how they signal
3. Know physiologic roles that she mentioned.

Back 60

Prof what's us to learn:
1. Mechanisms of synthesis, storage, release and inactivation of the 4NTs
2. Know the names of the important receptors and how they signal
3. Know physiologic roles that she mentioned.