ACh 1

Question 1

Acetylcholine

Answer 1

An ester of acetic acid and choline functions as a neurotransmitter

Question 2

Structure of acetylcholine

Answer 2

Diagram

Question 3

Different between acetylcholine and other small neurotransmitters such as GABA and glutamate

Answer 3

Not involved in metabolic pathways

Question 4

Behavioural processes involving acetylcholine

Answer 4

Arousal and attention

Question 5

Where is ACh used in the body?

Answer 5

Neuromuscular junction (paralysis, convulsions)
Autonomic nervous system (autonomic ganglia,
parasympathetic nervous system)
Central nervous system (arousal, attention, motivation)

Question 6

History of ACh

Answer 6

First neurotransmitters to be discovered

Otto Loewi confirmed ACh as neurotransmitter in 1921

Question 7

ACh and Henry Dale

Answer 7

In 1936, Henry Dale went on to demonstrate that
ACh is released when the motor nerve is
stimulated, activating voluntary, striated muscle
Dale used isolated leech muscles for his
experiments
Dale and Loewi won Nobel Prize in 1936

Question 8

function of ACh

Answer 8

Chemical synaptic transmission at the neuromuscular junctions of humans, mammals and some invertebrates
Chemical synaptic transmission in the human, mammalian and invertebrate brains
Chemical transmission in the human and mammalian
autonomic nervous systems
Non-neuronal signalling roles (skin, bone, immune cells)

Question 9

location of ACh

Answer 9

Diagram

Question 10

ACh synthesis

Answer 10

Diagram

Question 11

choline

Answer 11

is an essential nutrient

Question 12

acetylcoenzyme A

Answer 12

Is synthesised in the mitochondria

Question 13

Choline acetyltransferase

Answer 13

is the diagnostic marker for cholinergic neurons

no drugs target directly

Question 14

Vesicular Acetylcholine

Transporter (VAChT)

Answer 14

loads

acetylcholine into vesicles

Question 15

Botulinum toxin

Answer 15

Produced by Clostridium botulinum ( gram-negative)

inhibits release of ACh, causing muscle paralysis and death

Question 16

latrotoxin

Answer 16

Black widow spider venom; increases ACh release, leading to pain, cramps, sweating and fast pulse

Question 17

ACh catabolism

Answer 17

Diagram

Question 18

AChE

Answer 18

AChE is widely distributed in nerve
(synaptic cleft) and muscle but is also present in other tissues such
as red blood cells
AChE has very high catalytic activity: each molecule degrades
25,000 molecules of ACh per second!!

Question 19

ACh synapses

Answer 19

Short, fast bursts

Question 20

BChE

Answer 20

Butyrylcholinesterase (BChE)
is also known as
pseudocholinesterase
BChE is a nonspecific
cholinesterase enzyme 
BChE is mainly found in
blood (but also brain)

Question 21

Cholinergic receptors

Answer 21

Two families, nicotinic and muscarinic

Question 22

Langley 1905

Answer 22

1st to talk about receptors as mediators to cell responses

Question 23

Dale 1914

Answer 23

muscarine and
nicotine only partially
mimicked ACh effects

Question 24

Muscarine

Answer 24

Muscarine is a drug extracted from the fly agaric mushroom Amanita muscaria (hallucinogenic); Muscarine is a non-selective agonist of the muscarinic acetylcholine receptor (mAChR);
Muscarine poisoning causes miosis, increased salivation, lacrimation, excessive sweating,
abdominal cramping, diarrhoea, bradycardia, bronchconstriction

Question 25

CNS mAChRs

Answer 25

regulate many important functions such as cognitive, behavioural, sensory, motor and autonomic processes

Question 26

Peripheral mAChRs

Answer 26

mediate Ach effects in parasympathetic nervous system (e.g. decrease heart rate, increase smooth-muscle contractility and glandular secretion)

Question 27

Muscarinic receptors

Answer 27

G-protein-coupled receptors; metabotropic, and affect neurons and other cells over a longer time frame; M1-M5

Question 28

Where are M1,4,5 mainly expressed?

Answer 28

mainly expressed in the | CNS

Question 29

Where are M1,4,5 mainly expressed?

Answer 29

widely distributed in the CNS and peripheral tissues

Question 30

Mechanism of action of muscarinic receptors

Answer 30

Diagram

Question 31

Specific function of different muscarinic receptors

Answer 31

Table

Question 32

Agonists of muscarinic receptors are

Answer 32

Parasympathomimetic

Question 33

Antagonists of muscarinic receptors are

Answer 33

Parasympatholytic | tend to be non-selective for subtype

Question 34

Examples of muscarinic receptor antagonists

Answer 34

Oxybutynin for overactive bladder and incontinence (M1-3) Ipratropium for asthma and COPD (derivative of atropine, entirely non-selective but only works locally due to ROA)

Question 35

Atropine

Answer 35

Competitive, reversible antagonist of muscarinic receptors (non-selective) Atropa belladonna causes mydriasis, tachycardia, urinary, retention, constipation, dry mouth used in surgery as an antidote to nerve agent and pesticide poisoning

Question 36

Muscarinic receptors as drug targets

Answer 36

Table

Question 37

Nicotine

Answer 37

Non-selective agonist of nicotinic ACh receptor Nicotine binds muscle and neuronal nAChRs in the peripheral and central nervous systems agonism/antagonism is dose-dependent

Question 38

Nicotinic receptors

Answer 38

``` The nAChRs function as acetylcholine-gated cation channels; nAChRs are ionotropic receptors permeable to sodium, potassium and calcium ions. Two types: muscular and neuronal Expressed in the central and peripheral nervous systems, both presynaptically and postsynaptically Selectively blocked by hexamethonium ```

Question 39

which ion are nicotinic receptors most permeable to at the neuromuscular junction?

Answer 39

Potassium

Question 40

Neuronal nicotinic receptors

Answer 40

Neuronal nAChRs are comprised of combinations of the α2-α10 and β2-β4 subunits Can form homomeric or heteromeric receptors The different receptor stoichiometry configurations confer differences in calcium permeability and agonist and antagonist sensitivity between different receptors

Question 41

Homomeric neuronal nAChRs

Answer 41

Homomeric neuronal nAChRs • All five subunits are the same (α7, α9) • The α7 subunit is widely expressed throughout the mammalian CNS (higher level control) • In the CNS, the α9 subunit has been primarily identified in the inner ear cells

Question 42

Nicotinic receptors antagonists

Answer 42

``` Ganglionic blocking agents: act on the autonomic nervous system (e.g. TEA, used only in lab work now). • Neuromuscular (competitive) blocking agents: act on neuromuscular junction (e.g. tubocurarine). • Centrally-acting compounds (e.g. bupropion, mecamylamine) to help people stop smoking ```

Question 43

combined nicotinic and muscarinic responses in the ganglia, and CNS?

Answer 43

Look up

Question 44

Changing ACh levels

Answer 44

unable to modulate ChAT or VAChT No evidence that increase dietary Choline changes ACh levels Increase levels of synaptically available Ach by preventing breakdown –> Cholinesterase Inhibitors

Question 45

Acetylcholinesterase inhibitors

Answer 45

3 main groups: – Short-acting – edrophonium: reversible, brief action (10 min), used to diagnose myasthenia gravis. – Medium-acting (1-2h) – neostigmine, physostigmine; reversible, broken down more slowly, used to treat myasthenia gravis and glaucoma. – Irreversible – used as pesticides (organophosphates - malathion) or chemical weapons (VX, Novichok). Centrally acting- AD

Question 46

Acetylcholinesterase inhibitors

Answer 46

Side effects: Actions on parasympathetic nervous system (bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, decrease intraocular pressure); SLUDGE syndrome (Salivation, Lacrimation, Urination, Diaphoresis, Gastrointestinal upset and Emesis); Prolonged muscle contraction.

Question 47

Snake venom

Answer 47

Fasciculins are toxic proteins found in mamba snake venom; They bind to AChE, blocking its activity; They cause intense muscle fasciculation thus paralysing and/or killing prey

Question 48

Physostigmine

Answer 48

Eserine (physostigmine) from the Calabar bean was originally used as a test for witchcraft; Reversible cholinesterase inhibitor • Now used to treat glaucoma, (myasthenia gravis, Alzheimer’s disease, delayed gastric emptying now with neostigmine); Antidote for anticholinergic drug overdoses (e.g. atropine)

Question 49

Irreversible AChE inhibitors

Answer 49

Sarin gas (chemical weapon) is an inhibitor of AChE • Commonly used insecticides (malathion, organophosphates) have a similar effect • Cause SLUDGE – then death by cardiac failure • Reactivators of the irreversibly blocked enzyme (e.g. pralidoxime) developed as snake bite antidotes and protection against nerve agents

Question 50

Pralidoxime action

Answer 50

1) Organophosphate is bound to “esteric site” of AchE 2) Pralidoxime binds to “anionic site” of AchE and to organophosphate 3) Organophosphatedetaches from AchE