Lesson 12 Acetylcholine

ACh role in PNS (2)

Neuromuscular junction & ANS

ACh role in the CNS (2)

Behavioral & cognitive roles

Note: CNS has lower amounts of ACh than the PNS has

What are the effects of too much or two little ACh?

• Too little ACh → muscle weakness, paralysis, cognitive deficits

• Too much ACh → overstimulation, convulsions, respiratory failure

Curare causes muscular paralysis by…

Blocking nicotinic ACh receptors at the neuromuscular junction

Curare does not alter consciousness because… (2)

It does not cross the BBB & CNS cholinergic signaling is still intact

What is the synthesis pathway of the ACh, and how is it different from other systems?

• Choline + Acetyl-CoA → ChAT (enzyme) → Acetylcholine

• Synthesized in one step instead of multiple

_____ can be used as a histological marker to identify cholinergic neurons because it is only found in cholinergic neurons

ChAT

How do we get choline in the body? (2)

Through dietary fats & synthesis in the liver

How do we get Acetyl-CoA in the body?

Metabolism of sugar & fats

Boosting choline intake (does/does not) improve Alzheimer’s symptoms

Does not, instead causes peripheral side effects only

Why is there not many pharmacological uses for ChAT?

Hard to find a selective inhibitor of ChAT, not clear if it is even useful

What is the transport protein of ACh?

VAChT (vesicular acetylcholine transporter)

What is the mechanism (1) & effects of the drug Vesamicol (3)?

• Mechanism:

  • VAChT inhibitor

• Effects:

  • ↓ ACh inside vesicles

  • ↑ ACh remaining in cytoplasm

  • Synaptic vesicles main source of ACh release → less ACh release during neuronal firing

How does toxin from black widow spiders alter ACh release?

Massive ACh release in PNS → cholinergic overstimulation (tremors, muscle pain, etc.)

How does botulinum toxin effect ACh release?

Prevents synaptic vesicle fusion w/ presynaptic membrane  → muscle paralysis

What are clinical uses of botulinum toxin? (2)

• Botox  → reduces wrinkles in skin

• Analgesic effects in chronic pain disorders

What does the eznyme AChE do?

Degrades ACh into choline & acetic acid (breakdown)

After ACh breakdown choline requires _____ _____ to be recycled

Choline transporter

Drug Hemicholinium-3 (HC-3) mechanism & effect

• Mechanism: blocks choline uptake

• ↓ ACh synthesis

Choline transpoter KO mice

Die soon after birth, failure of neuromuscular transmission from lack of ACh synthesis → respiratory failure

AChE inhibitor effects

• Prevent ACh breakdown

• Can be beneficial for ppl who are deficient in ACh, however too much ACh can result in fatality

AChE inhibitor effects depend on… (3)

• Dose

• Reversibility

• Ability to cross BBB

How do AChE inhibitors work for patients with dementia?

• Increase availability of remaining ACh

• Help the effects of cholinergic neuron loss in the forebrain

What are the effects of pyridostigimine (natural AChE inhibitor) and where does it come from?

• Topical treatment for glaucoma

• Toxic effects (able to cross BBB)

• It is from calabar beans

What are the effects of organophosphates (AChE inhibitor)

• Permanent AChE inhibitor

• Extreme overstimulation, muscle paralysis, respiratory failure

Myasthenia Gravis

• Autoimmune disorder → antibodies attack nicotinic ACh receptors on muscle → reduced muscle responsiveness

• Symptoms: muscle weakness, fatigue, drooping eyelids, difficulty breathing or speaking

• Treatment: AChE inhibitors (pyridostigmine, neostigmine)

Congenital Myasthenic Syndromes

• Genetic disorder present at infancy

• Effect: ChAT deficiency → low ACh release, AChE deficiency → receptor desensitization

• Symptoms: muscle weakness, respiratory distress, apnea

• Treatment depends on cause:

  • ChAT deficiency → AChE inhibitors help

  • AChE deficiency → AChE inhibitors worsen symptoms

AChE is very important for the synthesis of ACh because…

Without it there would be no precursors to make more ACh

Donepezil/Aricept mechanism & effect

Reversible AChE inhibitor

Treats Alzheimer’s by boosting ACh

Sarin/Soman mechanism & effect

Reversible AChE inhibitor

Treats Myasthenia Gravis, protects against nerve gas

Nicotinic (nAChR) receptors structure & signaling

Structure: Ionotropic, 5 subunits

Signaling: ACh binds → channel opens rapidly → Na+ & Ca2+ enter the cell → depolarization & fast excitatory response

Muscarinic (mAChR) receptor structure & signaling

Structure: Metabotropic (M1-M5)

Signaling M1, M3, M5: Activate phosphoinositide system → excitation

Signaling M2, M4: Inhibit cAMP synthesis & opening K+ channels → inhibition

List the 5 subunit types of nAChR receptors

A, B, y, o, e

Homomeric nAChR

Same subunit

Heteromeric nAChR receptor

Different subunits

What nAChR subtype has the most affinity? What about the least?

High affinity: a4B2

Low affinity: a3B4

Changing nAChR receptor subtypes will change what? (3)

• Affinity & excitability

• Ion permeability → kinetics

• Overall function

a7 nAChR subtype ______ rapidly

Desensitizes

Different mAChR subtypes are coupled to different G-proteins which changes their ______

Function

M1, M3, & M5 are coupled to the _____ G-protein while M2 & M4 are coupled to the _____ G-protein

Gq, Gi

Describe nAChR functional states

1. Closed: No ACh bound; ion flow blocked

2. Open: Agonist bound; ions flow freely, causing depolarization

3. Desensitized: Prolonged exposure to an agonist causes the pore to close even if the agonist is still bound

nAChR functional state depolarization block

If the membrane stays depolarized too long, the cell loses its resting potential and cannot fire until the agonist is removed.

M4 & M5 regulates what when it come to DA neurons?

M4: Amount of ACh released onto DA neurons

M5: Receives M4 signal & modulates firing of DA neuron

nAChR are on presynaptic terminals where they…

Enhance the release of other neurotransmitters

Upregulation with nicotine use

Receptors desensitizes → brain compensates by increasing density of nAChRs on the cell surface

Botulinum Toxin

Inhibits ACh release; causes muscle paralysis. Used for muscle spasms and cosmetic Botox

Black Widow Venom

Massive release of ACh; causes tremors, muscle pain, and sweating

Succinylcholine

nAChR agonist that resists breakdown; induces depolarization block and paralysis for surgery

Mecamylamine

Neuronal nAChR antagonist; used experimentally and formerly for hypertension

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