Inhibitory Amino Acids

Question 1

What is the most predominant inhibitory neurotransmitter in the brain?

Answer 1

GABA

Question 2

What is the second, and less major, inhibitory neurotransmitter?

Answer 2

glycine

Question 3

What does GABA stand for?

Answer 3

gamma-amino-butryic-acid

Question 4

Why does almost every neuron in the the CNS have GABA synapses?

Answer 4

Because GABA is the primary braking system of the brain; it keeps the firing rate of neurons in check

Question 5

What are the two types of GABAergic neurons?

Answer 5

1. Projection neurons

2. interneurons

Question 6

What are projection neurons?

Answer 6

Neurons whose cell bodies reside in one nucleus, and whose terminals end in another nucleus

Question 7

What are interneurons?

Answer 7

Neurons who exist within a singular nucleus

Question 8

When was GABA first discovered as a neurotransmitter?

Answer 8

In the 1950’s

Question 9

What is GABA synthesized from? Which enzyme is primarily responsible for its synthesis?

Answer 9

from glutamate; glutamic acid decarboxylase (aka GAD)

Question 10

What are the two kinds of enzymes that synthesize GABA from glutamate?

Answer 10

1. GAD65
2. GAD67
   - both of these are named after their weight

Question 11

What does GAD need to synthesize GABA?

Answer 11

It needs a cofactor, vitamin B6

Question 12

What does GAD’s cofactor allow it to help with?

Answer 12

Increasing the affinity of glutamate

Question 13

How, and by what mechanism, is GABA taken into the vesicle?

Answer 13

GABA is taken up into the vesicle via an active transporter, vesicular GABA transporter (GAT)

Question 14

Which force allows GABA to enter the vesicle?

Answer 14

Through both electrostatic and diffusional forces (the active transporter depends on an ion gradient, helped by an antiporter)

Question 15

How is GABA released from the vesicle?

Answer 15

Through exocytosis

Question 16

How is GABA’s signal primarily terminated?

Answer 16

Through reuptake via the GABA transporter (GAT but NOT vesicular GAT) either on the presynaptic neuron, or nearby glial cells

Question 17

What is another method of GABA signal termination?

Answer 17

Termination via the enzyme GABA-transaminase (GABA-T)

- is a synthetic metabolic enzyme

Question 18

What are the two families of GABA receptors?

Answer 18

1. GABAa

2. GABAb

Question 19

What type of receptor are GABAa receptors?

Answer 19

They are ligand-gated ion chanels (their response is almost immediate)

Question 20

What kind of receptors are GABAb receptors?

Answer 20

G-Protein Coupled Receptors (because their responses take hundreds of milliseconds)

Question 21

Describe GABAa receptors?

Answer 21

• GABAa receptors are the primary focus of the inhibitory system because they are the most prevalent and are THE major inhibitor of the brain
• they contain 5 subunits
• they are permeable to Cl- ions (through diffusional forces only)
• net effect is inhibitory, because cell membrane is hyperpolarized

Question 22

Describe the various binding sites of the GABAa receptor?

Answer 22

It has a GABA binding site, a barbiturate binding site, a benzodiazepine binding site, a steroid binding site, and, within the channel, a picarotoxin binding site

Question 23

What is the effect of a picarotoxin?

Answer 23

It causes the body to seize and convulse, because the toxin is a GABAa channel blocker, so the inhibitory signal cannot be carried out (therefore, the body loses control and begins to convulse)

Question 24

Which GABA receptor does alcohol have an effect on (as we know that alcohol does not have its own binding site)?

Answer 24

GABAa

Question 25

How do benzodiazepines affect the GABAa receptor?

Answer 25

They facilitate the effects of bound GABA by causing the channel to become open wider, for a longer duration, allowing more than usual Cl- flow (and enhancing the inhibition signal)

Question 26

How do barbiturates affect the GABAa receptors?

Answer 26

The binding of barbiturates also opens the channel wider for a longer duration, but it doesn't need GABA to be bound to the active site in order to accomplish this - this leads to danger because now the brain has lost its ability to inhibit the signal being carried out by other neurons, and it has lost its feedback mechanism

Question 27

Why is it so dangerous to mix alcohol with barbiturates?

Answer 27

Because barbiturates don't need GABA bound in order to have an effect on the channel and because alcohol does not have its own binding site (and therefore also does not need for GABA to be bound to have an effect), as well as the fact that it disrupts the excitability of the neuron, over-inhibition follows, and the individual goes into a coma or dies as a result

Question 28

What are the three subunits of the GABAa receptors?

Answer 28

alpha, beta and gamma

Question 29

What effect do steroids have on GABAa receptors?

Answer 29

they open up the GABAa receptor more, allowing more Cl- flow into the membrane and causing a higher inhibitory effect

Question 30

What is the main difference between how benzodiazepines work on GABAa receptors, and how barbiturates act on GABAa receptors (exam question)?

Answer 30

The main difference is that benzodiazepines NEED GABA bound to the receptor in order to take effect, while barbiturates DO NOT NEED GABA to be bound to the receptor in order to have an effect

Question 31

Through what two processes do GABAa receptors adapt to an increased influx of inhibitory signals?

Answer 31

Through sensitization and downregulation

Question 32

What are some known ways that alcohol acts on the inhibitory system?

Answer 32

1. alcohol potentiates the GABAa currents (increasing Cl- flow) 2. alcohol inhibits NDMA response (decreasing Ca2+ flow)

Question 33

What is the classification for benzodiazepines acting on the GABAa receptors?

Answer 33

They are positive allosteric modulators that fall into three categories: 1. full allosteric modulators (FAM) (have a similar effect to agonists) 2. selective allosteric modulators (SAM) 3. partial allosteric modulators (PAM)

Question 34

Describe full allosteric modulators (FAM)? What are some medications that act in this way?

Answer 34

all of them act with high potency and high efficacy at a large number of GABA receptor types (therefore, they are not very highly selective) - these are the most dangerous, and the most addictive - example of FAMs is alprazolam (brand name xanax)

Question 35

Describe selective allosteric modulators (SAM)? What are some medications that act in this way?

Answer 35

all of them have a high potency and high efficacy, but act only on selective GABAa receptors - example of SAMs is diazepam (brand name valium)

Question 36

Describe partial allosteric modulators (PAM)? What are some medications that act in this way?

Answer 36

all of them have a high potency, but low efficacy (meaning fewer Cl- ions flowing in) and they only act on selective GABAa receptors - an example of PAMs is ambien or lunesta

Question 37

What is the main problem with FAMs and barbiturates?

Answer 37

They are memory eroding (because they inhibit LTP)