acetylcholine

roles of Ach

• contraction of skeletal muscles in PNS

• ANS

• brain - controls plasticity, arousal and reward

what are cholinergic neurones

neurones that synthesise and release Ach

how is Ach synthesised

• in presynaptic terminals of cholinergic neurones

• choline and actyl-CoA

how is Ach released

action potential arrives → depolarisation of plasma membrane → Ach released via exocytosis

what happens to Ach in synaptic cleft

binds to specific cholinergic receptors to produce either excitatory or inhibitory postsynaptic effects 

how is Ach removed from the synaptic cleft

by enzyme acetylcholinesterase and choline is taken up by specific transporter

explain this diagram (key enzymes for synthesis and removal of Ach)

1) choline acetyltransferase makes Ach from choline and acetyl CoA

2) acetylcholinesterase removes Ach from the synaptic cleft

3) choline is taken up by specific transporter

what are the 2 main classes of receptors that Ach acts on

• nicotinic (stimulated by nicotine, blocked by curare)

• muscarinic (stimulated by muscarine, blocked by atropine)

what are nicotinic Ach receptors

ligand-gated ion channels

how does depolarisation occur in nicotinic Ach receptors

undergo conformational change when Ach binds → change in shape leads to opening of central ion channel pore → influx of Na+ ions into postsynaptic cell → depolarisation → excitation of postsynaptic cell

what are muscarinic Ach receptors

G-protein coupled receptors

how many groups of muscarinic receptors are there

5 groups

• M1

• M2

• M3

• M4

• M5

which types of muscarinic receptors activate G_q/11 heterotrimeric class G of proteins

• M1

• M3

• M5

muscarinic receptor signalling cascade (M1, M3, M5)

what happens when Ach binds to M1, M3 or M5 receptors

receptor activates a Gq/11 class G-protein

what does the activation of the Gq/11 protein cause

causes alpha-subunit of G-protein to dissociate from βγ subunits.

after dissociation, what does the α-subunit of Gq/11 do

binds to and activates phospholipase C (plc)

what is the function of phospholipase C (PLC) in this signaling pathway

PLC breaks down the membrane phospholipid PIP₂ (phosphatidylinositol 4,5-bisphosphate) into two second messengers: IP₃ and DAG

what does IP₃ do inside the cell

IP₃ binds to IP₃ receptors on the endoplasmic reticulum, causing release of Ca²⁺ from intracellular stores

what is the effect of increased intracellular Ca²⁺ levels

rise in Ca²⁺ contributes to neuronal depolarization and enhances excitability

what is the role of DAG in the Gq/11 pathway

DAG activates protein kinase C (PKC), which phosphorylates various target proteins that modulate ion channels and signaling pathways

how do IP₃ and DAG together influence the postsynaptic neuron

they cause a slow depolarizing excitatory postsynaptic potential (EPSP) through Ca²⁺ release and PKC activation

what is the overall effect of M1, M3, and M5 receptor activation on the neuron

excitation of postsynaptic neurone via slow depolarisation

how does activation of M1, M3 or M5 receptors lead to neuronal excitation: SUMMARY OF CASCADE

upon ACh binding, the receptor activates the Gq/11 protein, causing the α-subunit to dissociate and stimulate phospholipase C (PLC) → PLC produces IP3 and DAG → IP3 triggers Ca²⁺ release from intracellular stores, and DAG activates protein kinase C (PKC) → these events cause a slow depolarizing EPSP, leading to excitation of the postsynaptic neuron

why do M2 and M4 receptors have the opposite effect

because they activate Gi/O heterotrimeric G proteins

how does M2 and M4 receptors cause an overall inhibitory effect when Ach binds

Ach binds → α subunit of these G-proteins disassociate from the βγ subunits → α subunit binds to adenylyl cyclase → leads to inhibition of Ca2+ channels

what is the main source of Ach in the brain

nucleus basalis of meynert (nucleus located in basal forebrain)

what are axons of cholinergic neurones called

cholinergic fibres because they release Ach

where do the axons of these cholinergic neurones project in the brain

project to neocortex, hippocampus, amygdala

which receptors mediate positive effects of Ach on memory consolidation in neocortex

muscarinic M1 receptors

how does Ach influence neocortex

by activating M1 receptors, Ach enhances memory consolidation and supports cognitive processing

where do these cholinergic neurons project to regulate memory formation

to hippocampus

why is Ach release in hippocampus important

because it regulates memory formation and learning process

which brain region receives cholinergic projections that influence emotional processing

amydala

how does Ach affect amgydala

it modulates emotional responses and contributes to emotional aspects of memory

apart from major projection systems, where else is Ach released in the brain

from interneurons in the striatum (local circuit cells) and neurons in the dorsolateral tegmental nucleus of the midbrain

what is the function of striatal cholinergic interneurones

they modulate motor control and coordinate activity between dopaminergic and GABAergic systems in the basal ganglia

what are the main projection targets of dorsolateral tegmental nucleus

the thalamus and cerebellum

how do cholinergic projections to the thalamus affect brain function

they regulate sensory processing and attention by modulating thalamic relay activity

what is the role of cholinergic projections to cerebellum 

they regulate movement coordination and fine motor control

in summary, what are the main functional roles of Ach in the brain

• Memory consolidation (neocortex, hippocampus)

• Emotional regulation (amygdala)

• Sensory processing (thalamus)

• Motor coordination (striatum, cerebellum)

true or false: both muscarinic and nicotinic Ach receptors mediate activity in the autonomic nervous system

true

example of nicotinic receptor agonists

nicotine

what can excessive activation of nicotinic receptors by nicotine cause

convulsions due to overstimulation of CNS nicotinic receptors

convulsions are involuntary, rapid contracting and relaxing of muscles causing uncontrolled shaking or jerking of body

example of muscarinic receptor agonist

compounds found in amanita mushrooms (e.g. muscarine)

what are CNS effects of muscarinic receptor agonists

• vertigo

• confusion 

• weakness

• coma (at higher doses)

what are PNS effects of muscarinic receptor agonists

• salivation

• sweating 

• pupil contraction

• dyspnea

• abdominal pain

• diarrhoea

why do muscarinic agonists cause these PNS effects

they mimic parasympathetic stimulation by activating muscarinic receptors in target organs

what are 2 examples of muscarinic receptor antagonists

• atropine 

• scopolamine

what are the central effects of muscarinic receptor antagonists at therapeutic dose

• drowsiness 

• euphoria

• amnesia

• fatigue

what are the central effects of muscarinic antagonists at higher doses

• excitement

• restlessness

• hallucinations

why do muscarinic antagonists have mild anti-Parkinson effects

they block cholinergic activity in striatum, helping to rebalance dopamine and Ach levels

what are the peripheral effects of muscarinic antagonists

• Pupil dilation (mydriasis)

• Decreased salivation

• Reduced pharyngeal and respiratory secretions

• Increased heart rate (tachycardia)

• Decreased gut motility and secretion

• Decreased bladder tone

why do muscarinic antagonists cause pupil dilation and dry mouth

by blocking parasympathetic input to iris sphincter and salivary glands

what do anticholinesterase inhibitors do

they block acetylcholinesterase, preventing Ach breakdown and causing Ach accumulation at synapses

why can anticholinesterase inhibitors be toxic or lethal

because excess Ach overstimulates cholinergic receptors leading to convulsions, paralysis and respiratory failure

why is anticholinesterase used to treat myasthenia gravis

to enhance neuromuscular transmission

what are CNS effects of anticholinesterase poisoning

• slurred speed

• confusion

• loss of reflexes

• conculsions

what are the PNS effects of anticholinesterase poisoning

• pupil constriction

• watery nasal discharge

• nausea and vomiting

• sweating

• abdominal cramps and diarrhoea

why do anticholinesterases cause both CNS and PNS symptoms

because Ach accumulates throughout nervous system, overactivating both muscarinic and nicotinic receptors

summary of differences between cholinergic agonists, antagonists and anticholinesterase

• Agonists → mimic ACh and stimulate receptors.

• Antagonists → block ACh and inhibit receptor activity.

• Anticholinesterases → increase ACh levels by preventing its breakdown.