12A. Cholinergic neurotransmission Flashcards
6 important Neurotransmitters
The main processes involved in synthesis, storage and release of neurotransmitters
-> identify 1 - 4
1, uptake of precursors;
2, synthesis of transmitter;
3, uptake/transport of transmitter into vesicles;
4, degradation of surplus transmitter;
The main processes involved in synthesis, storage and release of neurotransmitters
-> identify 5 - 8
5, depolarisation by propagated action potential;
6, influx of Ca2+ in response to depolarisation;
7, release of transmitter by exocytosis;
8, diffusion to postsynaptic membrane;
The main processes involved in synthesis, storage and release of neurotransmitters
-> identify 9 - 13
9, interaction with postsynaptic receptors;
10, inactivation of transmitter;
11, reuptake of transmitter or
degradation products by nerve terminals;
12, uptake and release of transmitter by non-neuronal cells;
13, interaction with presynaptic receptors
What is Molecular Model of an Average SV>
How do Vesicular Neurotransmitter Transporters work?
1/ Transmitter uptake into vesicles
2/ Antiporters
3/ Secondary active transporters
4/ Proton gradient is generated by V-ATPases (proton pumps)
Proteins are involved in exocytosis
-> several bacterialvtoxins known to cause neurologic symptoms were proven to inhibit exocytosis by ____
cleaving specific SNARE proteins
Proteins are involved in exocytosis
-> mutation of yeast homologs of the ____ causes defects in membrane trafficking.
SNAREs
Proteins are involved in exocytosis
-> _____ spontaneously form a thermodynamically stable 1:1:1 complex.
syntaxin, synaptobrevin, and SNAP-25
What is synaptotagmin?
major calcium-binding protein
What does SNARE proteins include?
“SNAP REceptor”
Soluble NSF attachment proteins (SNAP)
N-ethylmaleimide-sensitive factor (NSF) ATPase
How do SNARE proteins work?
1/ Assembly of pre-fusion SNARE/SM protein complex
2/ Activation of pre-fusion SNARE/SM protein complex by complexin
3/ Ca2+-triggering of fusion-pore opening
4/ Fusion-pore expansion + NSF- & SNAP binding
5/ NSF-mediated SNARE-complex disassembly & vesicle recycling
What are 2 types of Neurotransmitter receptors
1/ Ligand-gated ion channels
2/ G protein-coupled receptors
Major neurotransmitters of the Autonomic nervous system
-> Where do we find cholinergic neurons?
1/ Neuromuscular junction
2/ Autonomic preganglionic fibers
3/ Parasympathetic postganglionic fibers - heart, glands, smooth muscle
2 important types of receptors binding to neurotransmitters in central nervous system?
- nicotinic receptors
- muscarinic receptors
Model of a cholinergic synapse
- High affinity choline uptake („low- affinity” choline uptake in all tissues, phospholipid synthesis)
- ACh synthesis: choline acetyltransferase
- ACh storage: a specific transporter
- ACh release
- ACh inactivation: ACh esterase
What is the inhibitor of the choline transporter?
Hemicholinium
An example of muscarinic agonist
Arecoline
2 examples of muscarinic antagonist
Atropine and benzotropine
What is the inhibitor of vesicular acetylcholine transporter?
Vesamicol
2 inhibitors of ACh release
Botulinus and tetanus toxins
What is the molecule stimulating ACh release
black window spider toxin
What are the 3 inhibitors of AChE?
(Acetylcholinesterase (AChE) is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions, especially in muscles and nerves)
Tacrine, galantamine and physostigmine
What are the 2 nicotinic antagonists?
Curare and mecamylamine
Model of a cholinergic synapse
-> What is the partial agonist at nicotinic receptors?
Vareniciline
What is the enzyme involving in ACh synthesis?
Choline acetyltransferase
What is the enzyme involving in ACh synthesis?
Choline acetyltransferase
What is the enzyme involving in ACh inactivation?
ACh esterase
What is the equation for synthesis of acetylcholine?
What are some characteristics of Synthesis of acetycholine?
*(66 – 70 Kda)
*Immunohistochemical mapping of cholinergic neurons *Cytoplasmic
*Not rate–limiting
What is the enzyme for Hydrolysis of acetylcholine?
Acetylcholineesterase
What is the equation for the Hydrolysis of acetylcholine?
What are characteristics of for hydrolysis of acetylcholine?
It’s catalytic efficiency (kcat/Km) approaches the diffusion limit, the enzyme cannot catalyze the reaction any better and is said to have reached ‘catalytic perfection.’
What are the 5 Cholinergic muscarinic receptors?
1/ M1(neural) Gq
2/ M2 (cardiac) Gi
3/ M3 (glandular/smooth muscle) Gq
4/ M4 Gi
5/ M5 Gq
Cholinergic muscarinic receptors
-> What are main locations of M1(neural) Gq?
1/ Autonomic ganglia (hydrochloric acid and intrinsic factor secretion)
2/ Glands: salivary, lacrimal, etc. Cerebral cortex
Cholinergic muscarinic receptors
-> What is Cellular response of M1(neural) Gq?
PLC = Phosphalipase C
IP3 = inositol 1,4,5-trisphosphate
Cholinergic muscarinic receptors
-> What are main locations of M2
(cardiac) Gi?
Heart: atria
CNS: widely distributed
Cholinergic muscarinic receptors
-> What is cellular response of M2
(cardiac) Gi?
Cholinergic muscarinic receptors
-> What are main locations of M3
(glandular/ smooth muscle) Gq?
1/ Exocrine glands: salivary, etc.
2/ Smooth muscle: gastrointestinal tract, eye, airways, bladder
3/ Blood vessels: endothelium
Cholinergic muscarinic receptors
-> What is cellular response of M3
(glandular/ smooth muscle) Gq?
Cholinergic muscarinic receptors
-> What are main locations of M4 Gi?
CNS
Cholinergic muscarinic receptors
-> What is cellular response of M4 Gi?
Cholinergic muscarinic receptors
-> What are main locations of M5 Gq?
1/ CNS: very localised expression in substantia nigra
2/ Salivary glands
3/ Iris/ciliary muscle
Cholinergic muscarinic receptors
-> What is the cellular response of M5 Gq?
Cholinergic muscarinic receptors
-> What is functional response of M2 (cardiac) Gi?
1/ Cardiac inhibition
2/ Neural inhibition
3/ Central muscarinic effects (e.g. tremor, hypothermia)
Cholinergic muscarinic receptors
-> What is functional response of M3 (glandular/ smooth muscle) Gq?
1/ Gastric, salivary secretion
2/ Gastrointestinal smooth muscle contraction
3/ Ocular accommodation
4/ Vasodilatation
What is an atropine?
Atropine is a naturally-occurring alkaloid isolated from the plant Atropa belladonna
The role of Nicotinic receptors
nausea, vomiting, headache, dizziness weakness, tremor pale face, collapsus
The role of Muscarinic receptors
S- Salivation
L- Lacrimation
U -Urinary frequency
D-Diarrhea
G- Gastrointestinal cramping
E- Emesis
M- Miosis
What happen if there is “Atropin overdose”?
- increased antimuscarinic side effects:
dilated pupils, warm, dry skin, tachycardia, tremor, ataxia, delirium, and coma
What is myasthenia gravis?
A neuromuscular junction disease that has autoantibodies to postsynaptic ACh receptor
What is dihydropyridine receptor (DHPR)?
L-type voltage-dependent calcium channel, functions in skeletal muscle as a voltage sensor
What is the mechanism of ryanodin receptor mutation?
altered kinetics of Ca2+ channels persistent large increase in [Ca+]I
-> malignant hyperthermia
What are the symptoms of malignant hyperthermia?
rare, life-threatening condition in which inhaled anesthetics or succinylcholine induce severe muscle contractions and hyperthermia.
What is the treatment of malignant hyperthermia?
dantrolene (a ryanodine receptor antagonist)
Excitation– contraction in the ventricular muscles
->
Dihydropyridine (DHP) receptor (L-type channel)
What is the treatment for Dihydropyridine (DHP) receptor (L-type channel)?
Antiarrhythmic antihypertensive drugs („calcium
channel blockers”)
What is the mechanism for Excitation– contraction in the ventricular muscles?
Depolarization
-> L-type Ca2+- channel (DHP receptor) activation
-> Ca2+ entry
-> Ca2+ induced Ca2+ release from sarcoplasmic reticulum
-> contraction
What is an Acetylcholine effect on atrial GIRK (G protein-gated inwardly rectifying K+ ) channels?
The binding of acetylcholine to its receptor causes the release of G protein βγ subunits, which diffuse to a site on neighboring GIRK channels to activate their opening.
The resulting increase in outward K+ current hyperpolarizes the cardiac cell, thereby lowering the heart rate.
What are the 2 types of cholinomimetic (cholinergic) drugs)?
1/ Direct-acting
2/ Indirect-acting (cholinesterase inhibitors)
Identify
1 - Muscarinic
2 - Nicotinic
Identify 1 - 2
1/ Choline esters (acetylcholine)
2/ Alkaloids (pilocarpine)
Identify 1 - 3
Importance of acetylcholinesterase in 3 areas
Physiological
Pharmacological – reversible inhibition
Toxicological – irreversible inhibition
Where can we find Reversible cholinesterase inhibitors?
-Therapy of Myasthenia gravis
-Therapy of Alzheimer disease
-Eye drops (Glaucoma)
Some Irreversible cholinesterase inhibitors?
Cholinergic Crisis
Organic phosphate molecules
for example: Diisopropyl-flurophosphate (DFP)
What is the treatment for Irreversible cholinesterase inhibitors?
Cholinesterase reactivators (pralidoxime [PAM])
Pseudocholinesterase
- Intheplasma
– Produced by the liver - Hydrolysisofotheresters
–Short-lasting muscle relaxants (longer effect than acetylcholine)
What is Pseudocholinesterase deficiency?
a condition that makes you sensitive
to certain drugs used during anesthesia.
(The drugs are designed to briefly relax your muscles during a medical procedure.
With PD, the muscles stay relaxed for a longer time, which can lead to medical complications.
Genetic testing)
