What other ways can a drug affect neuronal transmission?

Question 1

What is neurotransmission?

Answer 1

An umbrella term that refers to anything affecting 1) neuron firing, 2) neurotransmitter release, or 3) receptor actions
- it refers to all actions at the synapse

Question 2

What happened in 1952?

Answer 2

Fatt and Katz placed electrodes at the neuromuscular junction to record the muscle activity with no stimulation

• they discovered that the voltage change of the electrode always increased/decreased quantally (by a factor of the minimum voltage)
• thus, they concluded that neurotransmitter release must also be quantal, in discrete packages

Question 3

What does quantal mean?

Answer 3

By a factor of something, and not anything in between

Question 4

What neurotransmitter do most neurons at the neuromuscular junction release?

Answer 4

Acetylcholine

Question 5

Which protein plays an important role in ACh release?

Answer 5

Syntaxin

Question 6

What is the neuromuscular junction?

Answer 6

The point where neurons and muscles meet

Question 7

What effect does clostridium botulinum have on the body?

Answer 7

This bacteria can paralyze the body and even arrest respiration

Question 8

How does clostridium botulinum effect neurotransmission?

Answer 8

It releases a toxin into the post-synaptic neuron that halts the ability of syntaxin from aiding the vesicle containing ACh to get to the cleft, so that the vesicle cannot dock on the cleft

Question 9

What is syntaxin? What does syntaxin do?

Answer 9

Syntaxin is a protein found in the synapse of a neuron; this protein guides the vesicle towards the synaptic cleft to release its neurotransmitter

Question 10

What are vesicles?

Answer 10

The phospholipid bilayer packet within the synapse that contains the neurotransmitter

Question 11

Which compound is NECESSARY for the synthesis of ACh?

Answer 11

choline

Question 12

Why do we need a diet that contains a minimal amount of choline?

Answer 12

Because our body cannot produce choline on its own, but only minimal amounts are needed to synthesize ACh

Question 13

What are some foods containing choline?

Answer 13

Eggs, brains, kidneys, beans

Question 14

What is the reaction to synthesize ACh?

Answer 14

choline + acetyl coenzyme A together react to form ACh (via choline acetyltransferase)

OR

acetylcholine + co-enzyme A react to get back to choline

Question 15

Which compound is RESPONSIBLE for the synthesis of ACh?

Answer 15

choline acetyltransferase (ChAT)

Question 16

In what two ways would one need a choline supplement?

Answer 16

1. If one has a very poor diet

2. If one is pregnant

Question 17

What are docking proteins?

Answer 17

Proteins that sit on the vesicles

Question 18

What is one example of a docking protein?

Answer 18

Syntaxin

Question 19

What is Dale’s Law?

Answer 19

The law that states that one neuron only releases one type of neurotransmitter (although today we know that this law isn’t 100% accurate)

Question 20

What neurotransmitter would a cholinergic neuron release?

Answer 20

ACh

Question 21

Where does the synthesis of ACh take place?

Answer 21

In the mitochondria of the cholinergic cell

Question 22

How does the neurotransmitter get inside the vesicle?

Answer 22

Via the vesicular ACh transporter (for ACh)

Question 23

Describe the process of the vesicular ACh transporter bringing ACh into the cell?

Answer 23

The transporter swaps one hydrogen proton out for every one NT particle in
- uses indirect energy to swap out H+ for ACh, due to the concentration gradient of H+ being higher inside the cell vesicle compared to the outside

Question 24

How is hydrogen kept at a higher concentration inside the vesicle compared to the outside?

Answer 24

Via the proton antiporter (which pumps H+ into the cell using ATP)

Question 25

What are AChEIs (acetylcholine esterase inhibitors)?

Answer 25

A family of drugs that blocks the effect of the enzyme that breaks ACh down (AChE)

Question 26

How is ACh cleared from the synapse? Why does this have to be a quick process?

Answer 26

ACh is cleared by reuptake via one of two processes 1. LACU (low affinity choline uptake) - this has the same effect as if the choline particles were simply diffused back into the pre-synaptic neuron 2. HACU (high affinity choline uptake) - uses active transport to bring the choline up into the pre-synapse

Question 27

How is ACh primarily deactivated?

Answer 27

Via the enzyme acetylcholinesterase (which is located in the cleft of the neuron)

Question 28

What are the two classes of ACh receptors?

Answer 28

1. Nicotinic ACh receptors (nAChRs) | 2. Muscarinic ACh receptors (mAChRs)

Question 29

What kind of receptor type are nAChRs? Where are they primarily found?

Answer 29

They are ligand-gated ion channels; found primarily in the PNS (autonomic NS responsible for breathing, heart rate, smooth muscle contraction, digestion, etc)

Question 30

Which ions of the central pore of the nAChRs permeable to?

Answer 30

Na+, K+ and Ca2+ | - therefore, the binding of ACh on a nAChR is excitatory

Question 31

How many different subunits does a nAChR have? What is the implication of this?

Answer 31

there are 17 different types, each with a specific number of receptors within that type (ex. Alpha type has 10 different receptor types) - this means that nAChRs have an incredible amount of variability (10 to the 17th power)

Question 32

What are the health implications of nicotinic ACh?

Answer 32

it reduces Parkinson's tremors and improves memory in Alzheimer's

Question 33

What is curare?

Answer 33

It is a reversible (competitive) antagonist of nAChR that paralyzes - it removes the ability of ACh to act on the nAChR - the antidote for curare poisoning is an AChEI (which outcompetes the toxin)

Question 34

What kind of receptor type are mAChRs? Where are they primarily located?

Answer 34

They are G-Protein Coupled receptors; located primarily in the CNS

Question 35

How many subtypes of receptors are there?

Answer 35

5 subtypes of mAChRs: - M1 - M2 - M3 - M4 - M5

Question 36

Of the different subtypes of mAChRs, which are Gq type receptors? What second messenger pathway does this lead to?

Answer 36

M1, M3 and M5 are all GqPCRs | - this means that they activate the PIP2 pathway

Question 37

Of the different subtypes of mAChRs, which are Gi type receptors? What second messenger pathway does this lead to?

Answer 37

M2, M4 | - leads to inhibitory adenylyl cyclase pathway

Question 38

How are the mAChRs modulatory in their effects?

Answer 38

Because the pore is permeable to K+, Ca2+ and Cl- - it either opens or closes these channels, depending on the post-synaptic receptor (if it's an Modd receptor to activate PIP2 pathway, or Meven to activate inhibitory adenylyl cyclase pathway)

Question 39

Which mAChRs are most implicated in cognition?

Answer 39

M1 and M4

Question 40

Why is it so difficult for pharmacologists to treat Alzheimer's if we know that ACh is very important in the formation of memories?

Answer 40

The search for selective cholinergic agonists is very difficult, because the active site is highly conserved (meaning it is nearly identical across subtypes) - therefore, it is difficult to develop a drug for a mAChR implicated in memory without affecting a mAChR implicated in autonomic muscle control

Question 41

What are the two main anatomical abnormalities surrounding Alzheimer's patients?

Answer 41

1. plaques in the brain 2. tangles of nerves - excessive tau proteins cause the failure of the neurons in these two ways

Question 42

How can one attempt to treat Alzheimer's?

Answer 42

With AChEIs 1. Tachrine (but has a short half life) 2. Donepezil (longer half life but more severe side effects) 3. Memantine (a non-competitive antagonist)

Question 43

How do nerve agents work?

Answer 43

They phosphorylate AChE (deactivating it) therefore ACh floods the synapse, but the signal is not carried out due to the receptors already being activated with some ACh - this leads to muscle spasms alongside paralysis

Question 44

What are G-agents? What are some of the examples of G-agents?

Answer 44

G-agents were nerve agents developed by the Germans in the 20s and 30s (causes its effect due to inhalation) - some G-agents are: 1. Tabun 2. Sarin Gas 3. Soman Gas

Question 45

What are V-agents? What is one example of a V-agent?

Answer 45

V-agents were nerve agents developed by the Americans | - one V-agent developed was VX, which is the most toxic and most stable nerve agent (causes its effect topically)

Question 46

What is the antidote to nerve agents? Who was primarily responsible for its development?

Answer 46

The antidote is an autoinjector, with two compounds: - H16 (which reactivates AChE) - atropine (which is a muscarinic antagonist, blocking the effects of ACh while the AChE works to get rid of all the excess ACh)