BB30044: The Cholinergic System (SW)
Introduction:
Acetylcholine: first neurotransmitter discovered
In 1921, Otto Loewi stimulated the vagus nerve of one frog heart and
observed the reduction in heart rate. He applied a fluid sample from this
heart to another frog heart and observed a reduction in heart rate in this
recipient heart.
Inferred that synaptic signalling uses a chemical messenger that was
present in the transferred fluid. Named it Vagusstoff as it was released
from vagus nerve.
Henry Dale identified the chemical messenger as acetylcholine (ACh).
Jointly awarded the 1936 Nobel Prize for Medicine
ACh is a major transmitter in the ANS
Acetylcholine is a major neurotransmitter
outside of the brain, in the autonomic
nervous system (ANS). Acts in both:
Acetylcholine is the neurotransmitter
used the neuromuscular junctions—
released in order to activate muscles.
Acetylcholine is also a neurotransmitter
in the autonomic nervous system:
Internal transmitter for the
sympathetic nervous system, acts at
sympathetic ganglia (chain of neurons
outside spinal cord)
The final product released by the
parasympathetic nervous system at end
points of vagus nerve-derived signals for
decreased HR, bronchoconstriction, stimulation of peristalsis and
secretion.
Cholinergic Pathways in the Brain
Cholinergic innervation is widespread throughout the brain (not as
abundant as GABA or glutamate)
Cholinergic projection neurons (have cell bodies in one brain region and
project to another, so signal between different regions) occur in 2 main
loci:
1. Basal forebrain: role in memory and cognition. Comprised of nucleus
basalis and medial septal nucleus. Cholinergic neuron axons project into
the hippocampus, and these projections degenerate in AD.
2. Midbrain nuclei: roles in arousal, reward, motor control
Local cholinergic interneurons (short axons, mediate signalling within a
single brain region): striatum has the highest density of ACh in the brain
A Cholinergic Synapse
, ACh synthesised from Acetylcoenzyme A (from mitochondria) and choline
by ChAT (Choline AcetylTransferase)
ACh packaged into vesicles by Vesicular ACh Transporter (VAChT) –
mediated by proton exchange
Released by Ca2+-dependent exocytosis
Interacts with postsynaptic Muscuranic and/or Nicotinic receptors
Removed by degradation by Acetylcholinesterase (AChE) – such
breakdown via enzyme activity is unique amongst classical
neurotransmitters (glutamate, serotonin and GABA taken up by
transporters)
Choline recycled back into presynaptic terminal by Choline Transporter
(ChT) – Na+ symporter. Resythesis of acetylcholine.
Both Choline acetyltransferase and VAChT are unique to the cholinergic
system – they can therefore be used to identify cholinergic neurons in the
brain:
ChAT and VAChT immunoreactive neurons visualised in the basal
forebrain of postmortem human brains. Can observe degeneration of
these neurons in AD.
These markers were therefore crucial in identifying ACh as being
involved in early stages of AD.
Two classes of ACh receptors:
Aceytlcholine is a Choline molecule that has been
acetylated at the Oxygen atom (acetyl group = methyl
group CH3 + carbonyl CO). Made up of a quarternary
amines, nitrogen and oxygen atom (choline). Oxygen
atom has ester oxygen and methyl group CH3 added.
Muscarinic receptor (mAChR) is a GPCR (metabotropic) –
recognises the nitrogen and ester oxygen of ACh
Nicotinic receptor (nAChR) is a ligand-gated ion channel (ionotropic) –
recognises the nitrogen and CH3 of ACh
Selective agonists: both receptors bind to ACh, but muscarine ligand binds
specifically to muscarinic receptors and nicotine to nicotinic receptors.
Selective antagonists: muscarinic receptors can be blocked by Atropine ,
nicotinic receptors can be blocked by d-Tubocurarine.
Muscarinic receptors
5 subtypes of mAChR (M1-M5), coded for by 5 genes
7 transmembrane spanning GPCR with an extracellular N-terminus, large
intracellular loop between TM domains 5-6 and an intracellular C terminus.
Intracellular loop and intracellular C-terminus contain phosphorylation
sites
Aromatic amino acids such as tyrosine have been identified in the agonist
binding site, and these amino acids are found primarily in TM regions 3, 5,
6 & 7. The ACh binding site being within the TM domain suggests that the
binding site is buried within the membrane.
X-Ray crystallography used to identify molecular structure, e.g. binding
site identified by agonist tiotropium (occupies the site long enough to
make crystals, unlike ACh)
Introduction:
Acetylcholine: first neurotransmitter discovered
In 1921, Otto Loewi stimulated the vagus nerve of one frog heart and
observed the reduction in heart rate. He applied a fluid sample from this
heart to another frog heart and observed a reduction in heart rate in this
recipient heart.
Inferred that synaptic signalling uses a chemical messenger that was
present in the transferred fluid. Named it Vagusstoff as it was released
from vagus nerve.
Henry Dale identified the chemical messenger as acetylcholine (ACh).
Jointly awarded the 1936 Nobel Prize for Medicine
ACh is a major transmitter in the ANS
Acetylcholine is a major neurotransmitter
outside of the brain, in the autonomic
nervous system (ANS). Acts in both:
Acetylcholine is the neurotransmitter
used the neuromuscular junctions—
released in order to activate muscles.
Acetylcholine is also a neurotransmitter
in the autonomic nervous system:
Internal transmitter for the
sympathetic nervous system, acts at
sympathetic ganglia (chain of neurons
outside spinal cord)
The final product released by the
parasympathetic nervous system at end
points of vagus nerve-derived signals for
decreased HR, bronchoconstriction, stimulation of peristalsis and
secretion.
Cholinergic Pathways in the Brain
Cholinergic innervation is widespread throughout the brain (not as
abundant as GABA or glutamate)
Cholinergic projection neurons (have cell bodies in one brain region and
project to another, so signal between different regions) occur in 2 main
loci:
1. Basal forebrain: role in memory and cognition. Comprised of nucleus
basalis and medial septal nucleus. Cholinergic neuron axons project into
the hippocampus, and these projections degenerate in AD.
2. Midbrain nuclei: roles in arousal, reward, motor control
Local cholinergic interneurons (short axons, mediate signalling within a
single brain region): striatum has the highest density of ACh in the brain
A Cholinergic Synapse
, ACh synthesised from Acetylcoenzyme A (from mitochondria) and choline
by ChAT (Choline AcetylTransferase)
ACh packaged into vesicles by Vesicular ACh Transporter (VAChT) –
mediated by proton exchange
Released by Ca2+-dependent exocytosis
Interacts with postsynaptic Muscuranic and/or Nicotinic receptors
Removed by degradation by Acetylcholinesterase (AChE) – such
breakdown via enzyme activity is unique amongst classical
neurotransmitters (glutamate, serotonin and GABA taken up by
transporters)
Choline recycled back into presynaptic terminal by Choline Transporter
(ChT) – Na+ symporter. Resythesis of acetylcholine.
Both Choline acetyltransferase and VAChT are unique to the cholinergic
system – they can therefore be used to identify cholinergic neurons in the
brain:
ChAT and VAChT immunoreactive neurons visualised in the basal
forebrain of postmortem human brains. Can observe degeneration of
these neurons in AD.
These markers were therefore crucial in identifying ACh as being
involved in early stages of AD.
Two classes of ACh receptors:
Aceytlcholine is a Choline molecule that has been
acetylated at the Oxygen atom (acetyl group = methyl
group CH3 + carbonyl CO). Made up of a quarternary
amines, nitrogen and oxygen atom (choline). Oxygen
atom has ester oxygen and methyl group CH3 added.
Muscarinic receptor (mAChR) is a GPCR (metabotropic) –
recognises the nitrogen and ester oxygen of ACh
Nicotinic receptor (nAChR) is a ligand-gated ion channel (ionotropic) –
recognises the nitrogen and CH3 of ACh
Selective agonists: both receptors bind to ACh, but muscarine ligand binds
specifically to muscarinic receptors and nicotine to nicotinic receptors.
Selective antagonists: muscarinic receptors can be blocked by Atropine ,
nicotinic receptors can be blocked by d-Tubocurarine.
Muscarinic receptors
5 subtypes of mAChR (M1-M5), coded for by 5 genes
7 transmembrane spanning GPCR with an extracellular N-terminus, large
intracellular loop between TM domains 5-6 and an intracellular C terminus.
Intracellular loop and intracellular C-terminus contain phosphorylation
sites
Aromatic amino acids such as tyrosine have been identified in the agonist
binding site, and these amino acids are found primarily in TM regions 3, 5,
6 & 7. The ACh binding site being within the TM domain suggests that the
binding site is buried within the membrane.
X-Ray crystallography used to identify molecular structure, e.g. binding
site identified by agonist tiotropium (occupies the site long enough to
make crystals, unlike ACh)
