Acetylcholine

Question 1

Formation of Acetylcholine?

Answer 1

Choline + Acetyl CoA——-> Acetylcholine + Coenzyme A.

• Via enzyme Choline acetyltransferase(ChAT).

Question 2

How can ACh move into vesicles and what is the role of Vesamicol?

Answer 2

• ACh moves into vesicles via vesicular ACh transporters( VACht).
• Vesamicol: blocks VACht, reduces amount of ACh released.

Question 3

Mechanism of Botulism.

• Clinical uses of botulism?

Answer 3

• Prevents fusion of synaptic vesicles with nerve terminal membrane.
  
  • In high dose, leading to muscle paralysis.
• Facial wrinkles, causes local paralysis, however must be repeated.

Question 4

How is the inactivation of Acetylcholine achieved?

What occurs to one of the products in its breakdown?

Answer 4

• Via enzyme Acetylcholinesterase(AChE).
  
  • —> choline and acetic acid.
• Pre-synaptic cell: metabolizes excess ACh that may have been synthesized.
• Post-synaptic cell; AChE, breaks down ACh after release in the synaptic cleft.

Choline is taken back up into cholinergic terminal.

Question 5

The function of Hemicolinium-3(HC-3).

Answer 5

• Blocking choline transporters in nerve terminal:
  
  • reducing ACh production.

without choline transporters; reduction of ACh release at the neuromuscular junction, causing breathing difficulties.

Question 6

Drugs that block AChE:

• Physostigmine(Eserine)?
• Neostigmine( Prostigmine)?

reversible or irreversible?

Answer 6

• Physostigmine: affect the CNS and cross the BBB.
• Neogstigme: does not cross the BBB.

Both are used to treat Myasthenia Gravis and are reversible AChE inhibitors.

Question 7

State some irreversible inhibitors of AChE?

what was used to reduce its effects?

Answer 7

• Sarin and Soman.
  
  • ACh overstimulation leads to muscle paralysis and death by aphyxiation.

Pyridostigmide bromide, reduced the effects sarin.

Question 8

Role of cholinergic cell bodies in the striatum?

Answer 8

• Regulation of movement with dopamine.

Question 9

Where can the origin of cholinergic innervations be located?

• Where do these innervations project to?
• Use of the cholinergic neurotoxin 192 igG-Saporin?

Answer 9

• Basal forebrain cholinergic system(BFCs).
  
  • projecting to the cortex, hippocampus, and regions of the limbic system.

Saporin:

• binds to surface protein on BFCs, taking up the neurotoxin kills neurons and neighboring neurons are sparred.

Question 10

Effect of cholinergic neurons in the dorsolateral pons?

• What components do they activate?
• Function of other pathways originating from the dorsolateral pons?

Answer 10

• Excitatory influence on midbrain DA neurons:
  
  • Via activation of post-synaptic cholinergic receptors.
    
    • reinforce effects of nicotine.

Other pathways: to the thalamus and the brainstem,

• behavioural arousal , sensory processing and initiation of REM.

Question 11

Describe the role and characteristics of Nicotinic receptors?

Mechanism?

Answer 11

• Respond to nicotine.
• Ionotropic.
• ACh binds, channels open, allowing entry of Na+ and Ca2+.
  
  • inducing fast excitatory response.

Question 12

State the 3 nicotinic ACh receptors?

State the abundance of the subunits.

Answer 12

• Muscle nicotinic receptors.
• Neuronal α4β2 receptors.
• Neuronal α7.

10 alpha and 4 beta subunits.

Question 13

Results of continuous agonist exposure to nicotinic receptors?

response to long term exposure to agonist?

Answer 13

• Receptor becomes desensitized, and the channel remains closed.
  
  • Eventually, become desensitized after a short time.
  • not all receptors become desensitized.
• Long term exposure:
  
  • Depolarisation block , resting potential lost, and the cell cannot be excited till agonist is removed and the membrane is repolarized.

Question 14

Agonists and Antagonists of Nicotinic ACh receptors?

• the function of Succinylcholine?
• The function of Mecamylamine?
• The function of D-tubocurarine?

and their roles in clinical settings?

Answer 14

Succinylcholine: muscle relaxant

• induces Depolarisation block, is an agonist, resistant to breakdown via AChE.

Mecamylamine: antihypertensive agent.

• Antagonist, blocking nicotinic receptors within CNS and autonomic ganglia.

D-tubocurarine: antagonists of muscle nicotinic receptors:

• a non-depolarising muscle relaxant.

Question 15

Role and characteristics of Muscarinic receptors?

mechanisms?

types?

Answer 15

• Metabotropic.
• Operate via secondary messengers:
  
  • M1-M3-M5: Gq.
  • M2 and M4: Gi.
• Other mechanisms: stimulation of K+opening , leading to hyperpolarisation.

Question 16

How do M1-M3-M5 secondary messenger work via Gq?

Answer 16

• Activation of PKC.
• Induces hydrolysis of PIP2, ——–> DAG + IP₃.
• IP₃ leads to Ca2+ increase in ER.

Question 17

How do M2 and M4 work as secondary messenger via Gi?

Answer 17

• Inhibits intracellular calcium release.

Question 18

The function of M5 receptors?

Result of M5 knockouts?

Answer 18

• Contribute to excitatory effects in DA neurons.
• Reward and dependence producing effects of drugs.
  • areas such as the hippocampus hypothalamus and midbrain.

Result of M5 knockouts:

• deficits in rewards in response to cocaine and morphine.

Question 19

location and function of M3 receptors as peripheral muscarinic receptors?

side effects of drugs influencing Muscarinic receptors?

Answer 19

• Located in smooth muscles and within ANS for salivation and lacrimation.
  
  • Activation induces muscle contraction.
• Activated by ACh release from postganglionic fibres of PNS.

side effects of administered drugs: dry mouth, due to blocking of peripheral muscarinic receptors.

Question 20

Location and function of M2 receptors?

Answer 20

• Located in cardiac muscle.
• Stimulation of PNS:
  • induces slow heart rate and decrease in contraction strength.