ACh Overview

Question 1

Acetylcholine

Answer 1

An ester of acetic acid and choline functions as a neurotransmitter

Question 2

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

Answer 2

Not involved in metabolic pathways

Question 3

Behavioural processes involving acetylcholine

Answer 3

Arousal and attention

Question 4

Where is ACh used in the body?

Answer 4

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

Question 5

function of ACh

Answer 5

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 6

location of ACh

Answer 6

Question 7

ACh synthesis

Answer 7

Question 8

choline

Answer 8

is an essential nutrient

Question 9

acetylcoenzyme A

Answer 9

Is synthesised in the mitochondria

Question 10

Choline acetyltransferase

Answer 10

is the diagnostic marker for cholinergic neurons (no drugs target directly)

Question 11

Vesicular Acetylcholine Transporter (VAChT)

Answer 11

loads acetylcholine into vesicles

Question 12

Botulinum toxin

Answer 12

Produced by Clostridium botulinum ( gram-negative) inhibits release of ACh, causing muscle paralysis and death

Question 13

latrotoxin

Answer 13

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

Question 14

ACh catabolism

Answer 14

Question 15

AChE

Answer 15

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 16

ACh synapses

Answer 16

Short, fast bursts

Question 17

BChE

Answer 17

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

Question 18

Cholinergic receptors

Answer 18

Two families, nicotinic and muscarinic

Question 19

Langley 1905

Answer 19

1st to talk about receptors as mediators to cell responses

Question 20

Dale 1914

Answer 20

muscarine and nicotine only partially mimicked ACh effects

Question 21

Muscarine

Answer 21

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 22

CNS mAChRs

Answer 22

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

Question 23

Peripheral mAChRs

Answer 23

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

Question 24

Muscarinic receptors

Answer 24

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

Question 25

Where are M1,4,5 mainly expressed?

Answer 25

mainly expressed in the CNS

Question 26

Where are M1,4,5 mainly expressed?

Answer 26

widely distributed in the CNS and peripheral tissues

Question 27

Mechanism of action of muscarinic receptors

Answer 27

Question 28

Specific function of different muscarinic receptors

Answer 28

Question 29

Agonists of muscarinic receptors are

Answer 29

Parasympathomimetic

Question 30

Antagonists of muscarinic receptors are

Answer 30

Parasympatholytic (tend to be non-selective for subtype)

Question 31

Examples of muscarinic receptor antagonists

Answer 31

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 32

Atropine

Answer 32

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 33

Muscarinic receptors as drug targets

Answer 33

Question 34

Nicotine

Answer 34

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 35

Nicotinic receptors

Answer 35

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 36

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

Answer 36

Potassium

Question 37

Neuronal nicotinic receptors

Answer 37

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 38

Homomeric neuronal nAChRs

Answer 38

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 39

Nicotinic receptors antagonists

Answer 39

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 40

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

Answer 40

Look up

Question 41

Changing ACh levels

Answer 41

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 42

Acetylcholinesterase inhibitors

Answer 42

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 43

Acetylcholinesterase inhibitors

Answer 43

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 44

Snake venom

Answer 44

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 45

Physostigmine

Answer 45

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 46

Irreversible AChE inhibitors

Answer 46

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 47

Pralidoxime action

Answer 47

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