Autonomic Nervous System Flashcards
What does the term cholinergic refer to?
synaptic transmission using acetylcholine (ACh) as a neurotransmitter
What does Acetylcholine’s positive charge mean?
- it will not dissolve in membranes
- also one of the structural features that is necessary for it to bind to its receptors
What is important in the breakdown of acetylcholine and why?
Ester linkage - it is the point at which the molecule is cleaved to terminate its synaptic action
What is Acetylcholine broken down by?
the enzyme acetylcholinesterase
What happens at cholinergic nerve terminals?
- Acetylcholine is broken down by the enzyme acetylcholinesterase
- The choline that is produced is then taken up by a choline transporter into the presynaptic terminal.
- Once in the terminal the enzyme choline acetyl transferase (located in the cytoplasm) catalyses the reaction between acetyl-coenzyme A and choline. The products are acetylcholine and free enzyme A
- The acetylcholine is then repackaged into vesicles by a specific acetylcholine transporter in the vesicle membrane
What is the basic mechanism of cholinergic transmission?
- Action potential approaches synapse
- Voltage sensitive Ca2+ channels open
- Ca2+ stimulates ACh vesicle fusion
- ACh released into synapse
- ACh activates postsynaptic receptor
- ACh broken down by AChE
What are ACh receptors divided into?
Muscarinic and nicotinic types
Give features of Nicotinic receptors including it’s structure, agonists and antagonists.
- Ligand gated ion channel
- Fast transmission
- Pentametic
- 16 subunits in humans (9 alpha, 4 Beta, gamma, delta and epsilon)
- Many receptor subtypes (subunit combinations)
- Built in ion channels
- 2+ ACh sites (at the interfaces of alpha subunits and their neighbouring subunit)
- Responses us-ms
- Agonists: nicotine, suxamethonium
- Antagonists: atracurium, tubocurarine, alpha BTX
Give features of Muscarinic receptors including it’s structure, agonists and antagonists.
- G-protein coupled
- Slow transmission
- Monomeric
- M1-5 subtypes
- 5 receptor types
- Binding site for G protein
- 1 ACh site along top of transmembrane domain
- Responses ms-s
- Agonists: Muscarine, pilocaripine,
- Antagonists: atropine, hyoscine
What are the tissues the Nicotinic receptors affect?
- NMJ (neuro-muscular junction)
- CNS
- Autonomic ganglia
What are the tissues muscarinic receptors affect?
- CNS
- Parasympathetic
- Sympathetic
What superfamily are nicotinic receptors part of?
The cys-loop receptor superfamily
What are the human receptor subunits that could be found in nicotinic receptors?
Alpha subunits numbers 1-10 (except with don’t have alpha 8 in humans) so we have 9
Beta subunits (1-4)
Gamma, epsilon, and delta which are all similar to each-other so form one grouping
What is the structure of the Skeletal Muscle nAChR and what is it permeable to?
- Transmembrane subunits
- Would look like a ring if we viewed it from above
- Two alpha subunits, epsilon subunit, beta subunit and delta subunit (this is adult – in foetal it would be gamma instead of epsilon)
- The two binding sites are found in the interface between alpha subunit and neighbouring epsilon and delta subunit
- All channels are cation channels which are permeable to Na+, K+ and varying degree of Ca2+ permeability. Neuronal receptors more permeable than skeletal receptors to calcium
What isn’t expressed in neuronal tissue and what we we see expressed instead?
None of the skeletal muscle subunits (delta, epsilon, gamma) are expressed in neuronal tissue. Instead we see expression of alpha 2 – alpha 10 and beta 2 – beta 4
What subunits are found in brain nicotinic nicotinic receptors?
Either:
- 2x alpha 4, 3x beta 2
- 5x alpha 7 – homopentemer (5 acetylcholine binding sites)
What subunits are found in the autonomic ganglia nicotinic receptors?
alpha 3, beta 4
What subunits are found in the inner-ear hair cells nicotinic receptors?
alpha 9, alpha 10
Instead of fast synaptic transmission what role do nicotinic receptors play in the brain and why?
- their role is neuromodulation – modulate the release of acetylcholine and other neurotransmitters
- because in the brain transmission the subunits are mostly on pre-synaptic nerve terminals and neuronal axons instead of post-synaptic nerve terminals.
What happens in the sympathetic and parasympathetic nervous systems?
we have a two neuron chain leaving from the spinal cord to the effector tissue. The two neurons make a synapse in the autonomic ganglia. The preganglionic neuron (coming out of the spinal cord) releases acetylcholine. This diffuses to the cell bodies of the post-ganglionic neurones. On the cell bodies are nicotinic receptors which contain alpha 3 and beta 4 receptors. They trigger an action potential in the post-ganglionic neuron and ensure the signal is sent to the effector tissues
What happens at the skeletal neuromuscular junction?
Alpha motor neurons are a class of lower motor neurons that carry signals from the spinal cord and the brain stem to skeletal muscle. They are myelinated, large diameter neurons that are capable of very fast transmission
What transmembrane domain forms the lining of the ion channel in the nicotinic acetylcholine receptor subunit?
Transmembrane domain 2
What superfamily are muscarinic receptors part of and what are the defining features about this family?
• Part of GPCRs superfamily
- 7 transmembrane domains
- All signal through G-proteins
Give the family tree of the GPCR superfamily that leads to the muscarinic receptor
• GPCR superfamily:
- Family A receptors (Rhodopsin family)
- Muscarinic receptor (sub)family
- M1, M2, M3, M4, M5
What other important receptors are there in family A?
- Rhodopsin
- Adrenoceptors
- Angiotensin II receptors
- Dopamine receptors
- Histamine receptors
In a typical family A member where will you find the agonist binding sites?
At the top of the transmembrane domains in TM3, 5, 6 and 7 you find the agonist binding sites
Where will you find receptor M1, what is it’s pathway and selected roles?
- found in glands, cerebral cortex and autonomic ganglia
- it’s pathway is the IP3 (Gq) pathway
- Selected roles: cognition in cerebral cortex
What are the therapeutic targets and side effects for the M1 receptor?
- Using an agonist you can target Schizophrenia and Alzheimer’s
- using an antagonist you can target Cancer
- side effects may be cognitive issues
Where will you find receptor M2, what is it’s pathway and selected roles?
- found in the Heart, CNS and Smooth muscle
- Pathway: cAMP (Gi)
- Modulates heart rate (acetylcholine reduces heart rate)
- Modulates smooth muscle
What are the therapeutic targets and side effects for the M2 receptor?
- Antagonists can be used to target Bradycardia, Alzheimer’s and Depression
- A side effect when using an antagonist on someone with a normal heart rhythm is Tachycardia
Where will you find receptor M3, what is it’s pathway and selected roles?
- Found in glands, smooth muscle (eye, bronchial tract, blood vessels)
- pathway: IP3 (Gq)
- Roles: smooth muscle contraction, exocrine secretion (e.g. salvia and tears)
What are the therapeutic targets and side effects for the M3 receptor?
- Antagonists can be used to target an overactive bladder, asthma and IBS
- Agonists can be used to target Sjogren’s syndrome (autoimmune attack on certain glands – leads to dry eyes and mouths)
Glaucoma
T2DM - Antagonists can cause Dry mouth
Constipation
Worsen glaucoma
T2DM
Where will you find receptor M4, what is it’s pathway and selected roles?
- Found in CNs and Salivary gland
- Pathway: cAMP (Gi)
- Roles: salivary gland
What are the therapeutic targets and side effects for the M4 receptor?
- Agonists can help target drug addiction
- agonists can produce the side effects Hypersalivation (produced by antipsychotic drug clozapine) – produces antagonist effects at M1, 2, 3 and 5 receptors but is an agonist at M4 receptors
Where will you find receptor M5, what is it’s pathway and selected roles?
- Found in CNS
- Pathway: IP3 (Gq)
- Roles ??
What are the therapeutic targets for M5?
- antagonist can be used to target drug addiction
Why have very few selective or competitive agonists been produced for muscarinic receptors?
- because the agonist binding site is highly conserved in muscarinic subtypes - there is very few differences between amino acids
What have selective drugs been made for in muscarinic receptors?
- the allosteric site located a little above the binding site
- there is no natural agonist for it so it is much less conserved
How does Vesicular release work?
- Synaptobrevin, SNAP-24 are collectively known as SNARE proteins (SNAP Receptor)
- When intracellular calcium concentrations rise, the SNARE proteins bind to each other, drawing the vesicle close to the membrane
- The vesicle fuses with the membrane and the contents (ACh) are released into the synapse
What do the M2 and M4 receptors act as?
M2 and M4 receptors act as presynaptic auto-receptors. They inhibit the release of ACh from the presynaptic nerve terminal. This is a form of negative feedback
What is a post-synaptic cell?
This could be any tissue innervated by the parasympathetic nervous system e.g. smooth muscle, cardiac muscle, gland. It could also be another CNS neuron.
What are the two naturally occurring agonists in Nor(adrenergic) transmission?
Adrenaline and Noradrenaline
What are the main differences between Noradrenaline/Norepinephrine and Adrenaline/Epinephrine?
- Noradrenaline is primarily a neurotransmitter
- Adrenaline is mainly a hormone
What is the structure of adrenaline and noradrenaline?
- Virtually identical
- Adrenaline has an extra methyl group on it’s nitrogen
- Both have a Catechol group (members of the catecholamine family of compounds)
- Both have a chiral carbon (always in R configuration)
What are the main features of the adrenergic nerve terminal?
- Aromatic amino acid transporter at the top
- Mitochondrion
- COMT (catechol-O-methyltransferase)
- vesicle
- NET
What is the Aromatic amino acid transporter responsible for?
Bringing in the precursor to noradrenaline: tyrosine
What does the mitochondria do?
- It has Monoaminoxidase (MAO) present on it’s outer membrane
- this regulates the amount of noradrenaline present in the nerve terminal
What is COMT involved in?
The metabolism of adrenaline and noradrenaline
What happens with the vesicle?
- Transmitters released by vesicular release (happens in the same way as acetylcholine)
- VMAT (vesicular monoamine transporter) moves noradrenaline into the vesicles
What does NET do?
- Terminates the transmitter released into the synapse
- Transporter protein
- Uses the sodium and chloride gradients of the cell to move the neurotransmitter back into the cytoplasm and it can either then be metabolized by monoamine oxidase or recycled into the vesicles and used again
What happens to the recycled noradrenaline?
- About 75% of noradrenaline gets recycled into nerve terminals
- About 25% gets recycled and moved into astrocytes
What are the stages leading to either the production of adrenaline or Noradrenaline?
- Tyrosine (an amino acid) is the precursor for noradrenaline and adrenaline
- Transformed using tyrosine hydroxylase into a precursor compound L-DOPA.
- L-DOPA is the precursor for dopamine, noradrenaline and adrenaline
- If you have dopa decarboxylase L-DOPA is transformed into dopamine (also a precursor)
- then:
- If you have dopamine beta hydroxylase present you can make noradrenaline
- If you have phenylethanolamine N methyl transferase present you can make adrenaline
Why is the production of noradrenaline unique?
Dopamine beta hydroxylase is present in the membrane of neurotransmitters – not the cytoplasm so the production of noradrenaline is unique
Where is adrenaline mainly produced?
in the adrenal medulla
Which two enzymes are the targets of a series of drugs which are used to treat CNS disorders and which CNS disorders do they treat?
- monoamine oxidase
- catechol-O-methyltransferase
- Antidepressants target MAO
- Parkinson’s drugs target both
Who divided Adrenoceptors in alpha and beta?
Alquist in 1948
In terms of agonist potency what is the ranking of alpha and beta adrenoceptors?
- Alpha: noradrenaline > adrenaline > isoprenaline
- Beta: isoprenaline > adrenaline > noradrenaline
How many different subtypes of adrenoceptor are there and what are they?
- 9 each coded by a different gene
- a1A, a1B, a1D, a2A, a2B, a2C
- B1, B2, B3
What superfamily are Adrenergic receptors part of and what is their family tree?
• GPCR superfamily
- Family A receptors (Rhodopsin family)
- Adrenergic receptor (sub) family
- a1A, 1B, 1D
- a2A, 2B, 2C
- B1, 2, 3
What are the locations of the adrenergic neurons?
- Sympathetic nervous system: all 9 subtypes Fright, flight, fight responses - CNS: all except B3 Arousal and wakefulness Mood Blood pressure control
For the Adrenergic receptor subunit Alpha 1 what G protein is it coupled to and what is it’s function?
- coupled to Gaq (phospholipase C) + (stimulatory)
- functions:
• Vasoconstriction (increase BP) (use antagonists to block vasoconstriction and reduce BP)
• Contract visceral smooth muscle - Bladder sphincter
- Uterus
- Iris radial muscle
- Seminal tract
- Pilomotor muscles
• Relax GI tract
For the Adrenergic receptor subunit Alpha 2 what G protein is it coupled to and what is it’s function?
- coupled to Gai (adenylyl cyclase) - inhibitory
- functions
• Transmitter release
• Insulin release
For the Adrenergic receptor subunit Beta 1 what G protein is it coupled to and what is it’s function?
- Coupled to Gas (adenylyl cyclase) +
- functions
• Increased heart rate and force of contraction (use antagonist to decrease heart rate)
• Release of renin
• Lypolysis)
For the Adrenergic receptor subunit Beta 2 what G protein is it coupled to and what is it’s function?
- coupled to Gas (adenylyl cyclase) +
- Functions
• Bronchodilation (use agonist in asthma)
• Vasodilation (decrease BP)
• Relax visceral smooth muscle
• Lipolysis
• Glycogenolysis
• Muscle tremor
What is the structure of adrenoceptors?
- Have common 7 transmembrane domain
- Binding sites on top of transmembrane domain
- G protein site in the intracellular face of the membrane
- Folded into a compact shape
What are the selective antagonists for adrenoceptors?
- Labetalol non selective
- Phenoxybenzamine (insurmountable/ non-competitive)
- Phentolamine (competitive) and Chlorprozamine selective for alpha
- Propranolol selective for beta
- Doxasozin selective for a1
- Yohimbine selective for a2
- Atenolol selective for B1
- Butozamine selective for B2
What are the selective agonists for adrenoceptors?
- Adrenaline/noradrenaline non selective
- Methoxamine – alpha selective
- Isoprenaline – beta selective
- Phenylephrine – alpha 1 selective
- Clonidine – a2 selective
- Dobutamine – B1 selective
- Salbutamol, Salmeterol – B2 selective
Which drugs act on adrenergic transmission?
- Cardiovascular system (diverse)
- Anti-asthma drugs
- Decongestants
- Aphrodisiacs
- Migraine
- ADHD
- Depression
What are some fight or flight responses?
- Increased heart rate (tachycardia)
- Increased blood pressure
- Increased blood flow to muscle
- Inhibits GI peristalsis
- (bronchial dilation)
- Pupil dilation
What happens with transmission in the sympathetic nervous system?
- In the sympathetic nervous system the first neurone has its cell body in the CNS. It makes a synapse with the second neurone in a ganglion – a collection of neuronal cell bodies outside the CNS. Transmission at this synapse is via nAChR. These receptors are of the a3b4 type
- The second neurone synapses with the target tissue. Transmission here is via noradrenaline acting on adrenergic receptors. Sympathetic ganglia are mostly located close to the spinal cord in a chain (paravertebral ganglia)
- Signal at motor synapse terminated by uptake of transmitter
What do the neurones that enter the adrenal medulla do?
The neurones that enter the adrenal medulla also pass through the paravertebral chain. They make synapses with cells that are like neurones with no axons. Instead of releasing neurotransmitter into a synapse, these adrenal medulla cells release it into the circulation to act in a hormonal manner
What are some rest and digest responses?
- Decreased heart rate (bradycardia)
- Increased GI motility
- Bronchial constriction
- Pupil constriction
- Gastric acid secretion
What is different in parasympathetic transmission at the ganglia?
at the effector tissue the transmitter is ACh and the receptor is the mAChR
How is the signal at the motor synapse in the parasympathetic system terminated?
By hydrolysis of transmitter
In the parasympathetic branch where are the ganglia located?
- away from the spinal cord, closer to the target tissue
Where is the parasympathetic output from the spinal cord confined to?
The medullary and sacral regions
What is ‘tone’?
The constant, underlying level of activity in a system
Where is tone frequently present?
in the autonomic nervous system
Give an example of tone?
the vagus nerve (a branch of the parasympathetic nervous system) constantly releases small amounts of acetylcholine onto one of its target tissues, the sinoatrial node. This has the effect of reducing the natural action potential rate of the SA node from around 100 bpm to about 70 bpm
