Autonomic synapses Flashcards
All somatic motor fibres release…
ACh on nAChr
All pre ganglionic fibres release …
ACh on nAChr on post ganglionic fibre
Post ganglionic parasympathetic fibres release …
ACh on muscarinic receptors
Post ganglionic sympathetic fibres release …
Noradrenaline on adrenergic receptors
Noradrenaline & neuropeptides on adrenergic/associated receptors
ACh on muscarinic (sweat glands only)
What is the innervation of sweat glands?
Sympathetic via ACh on muscarinic receptors
What is the only location of sympathetic response with ACh/Muscarinic receptors?
Sweat glands
What is muscarine?
Agonist for muscarinic receptors, doesn’t bind nAChrs
What is nicotine?
Agonist for nAChr, doesn’t bind to muscarinic receptors
What are muscarinic antagonists?
Atropine, cyclopentolate, hyoscoine
What is inhaled muscarinic antagonist?
Ipratromium bromide
How is atropine taken?
Orally or as injection
What is mecamylamine?
Block nicotinic receptor at ganglia
What condition can we use atropine for?
Bradycardia: acts on M2 on SAN and AVN
How do we treat urinary incontinence?
Darifenacin: M3 blocker, block smooth detrusor muscle contractions
What is pirenzipine and what do we use it for?
M1 blocker
Decrease stomach secretions and increase motility, used to treat ulcers
What 2 drugs affect autonomic ganglia?
Hexamethonium
Suxamethonium
What is the action of hexamethonium?
Non-depolarising ganglionic blocker, a nicotinic (nAChR) receptor antagonist.
What is the action of suxamethonium?
Depolarising drug, generates an action potential, AChE cannot remove the drug so the membrane cannot repolarise. The maintained depolarisation means that the voltage gated sodium channels are inactivated.
Where do preganglionic parasympathetic axons mainly arise from?
Brain stem
Are pre-ganglionic neurones myelinated?
Yes
Are post-ganglionic neurones myelinated?
No
What are the relative lengths of the sympathetic pre/post ganglionic neurones?
Preganglionic nerves are short and the postganglionic nerves are long.
What are the relative lengths of the parasympathetic pre/post ganglionic neurones?
Long preganglionic neurones and short postganglionic neurones
Where are the parasympathetic ganglia positioned?
Close to target
Do postganglionic autonomic neurones have end plates?
No
How do autonomic neurones innervate smooth and cardiac muscle?
Synapse en passant - vesicle containing varicosities along the axon, release NT
What is a varicosity?
Bulbous vesicle filled enlargements of the neurone
True or false, catecholamines are always excitatory?
True
Where is adrenaline released from?
Adrenal glands (adrenal medulla) chromaffin cells
Describe different locations of Adr and NA release?
NA: main neurotransmitter released by post ganglionic symp fibres
Adr: main hormone released by adrenal medulla
How are catecholamines synthesised?
Tyrosine - L dopa - Dopamine - NA - Adr
What converts NA to ADR?
Phenlethanolamine-N-methyltransferase (PNMT)
What is rate limiting step in Na or Adr formation?
Tyrosine - L dopa by Tyrosine hydroxylase
What converts Tyrosine to L-dopa?
Tyrosine hydroxylase
What converts L-dopa to dopamine?
DOPA decarboxylase
How is the rate limiting step of catecholamine synthesis regulated?
Phosphorylation and feedback inhibition by noradrenaline.
Noradrenaline competes for THBP co-factor site when high (inhibits production)
What step of catecholamine synthesis is most commonly regulated and why?
Tyrosine - L-dopa
It is the rate limiting step
What co-factors are needed for the limiting step of catecholamine synthesis?
THBP, Fe2+
How is the catecholamine synthesis pathway different in the PNS than the CNS?
In the CNS the pathway terminates at dopamine
However in the PNS the dopamine is moved to storage vesicles - other enzymes convert to NA/Adr
What enzyme converts Dopamine to NA?
Dopamine beta-hydroxylase
How does tyrosine enter neurone?
Active transport into neurone via Na+ dependent carrier
What happens to NA and Adr normally after release and binding to receptor?
Actively transported into presynaptic neurone and broken down
What is chemical change from NA to Adr?
Methyl group added
Where is PNMT found?
Adrenal medulla chromaffin cells (not symp fibres)
What is VMAT?
Transporter that transports dopamine and noradrenaline after synthesis from cytosol into vesicle
Where is adrenaline made in cell?
Cytoplasm
Describe potencies of agonists for alpha 1 receptor
Noradrenaline > adrenaline > isoprenaline
Describe potencies for beta 1
Isoprenaline > adrenaline > noradrenaline (marginal)
Describe potencies for beta 2
Isoprenaline > adrenaline > noradrenaline
What is isoprenaline?
Non selective beta agonist
How are NA and Adr transported back into vesicles?
By monoamine transporter (VMAT2)
Protects from monoamine oxidases which catalyses its inactivation in the cytoplasm
Describe how noradrenaline is taken back into presynaptic neurone but also surrounding tissue?
Reabsorbed via uptake 1 but can be reabsorbed to surrounding tissue by reuptake 2
Uptake 1 more NA specific, Uptake 2 takes more Adr than uptake 1
What happens to most NA reabsorbed into presynaptic terminal?
Inactivated by Monoamine oxidase and recycled
What happens to NA and Adr reabsorbed into surrounding tissue?
Inactivated by COMT (Not found presynaptically)
Where in cell is monoamine oxidase found?
Outer mitochondrial membrane and also extracellularly
Most Ad and NA in circulation metabolised by?
COMT
Where is COMT found?
Liver kidney, circulation etc
What do amphetamines do?
Inhibit uptake 1 mechanism - prolonged NA activity - hypertension
What do MAO inhibitors do?
Inhibit MAO so decrease breakdown of NA etc so increased availability
Describe different isoforms of MAO
MAO- A preferentially breaks down adrenaline
MAO-B noradrenaline
What is the name of a tyrosine hydroxylase inhibitor, why would you use?
Alpha-methyltyrosine, reduces amount of transmitter.
What is the name of a DOPA decarboxylase inhibitor, why would you use?
Carbidopa, peripheral inhibitor of DOPA decarboxylase, reduces peripheral side effects in L-DOPA therapy (parkinsons disease)
What is the name of a dopamine beta-hydroxylase inhibitor, why would you use?
Disulfiram, reduces noradrenaline / adrenaline synthesis.
How do you treat Parkinson’s disease?
L-DOPA therapy, increases dopamine/noradrenaline and adrenaline synthesis.
Increases brain dopamine in Parkinson’s disease, L-DOPA can pass the blood brain barrier.
What type of GPCR is each adrenergic receptor?
Α1 Gq
Α2 Gi
Β1 Gs
Β2 Gs
Β3 Gs
Where is each type of adrenergic receptor located?
Α1 Ureter, uterus, sphincter, iris dilator muscles, seminal tract.
Α2 Post-ganglionic sympathetic neurones (pre-synaptic neurone). There are also some present on the post-synapse.
Β1 Cardiac cells, kidneys.
Β2 Bronchioles, veins, GI tract, pancreas , hepatocytes. Skeletal muscle.
Β3 Adipose tissue, detrusor muscle in bladder.
What is the effect of each type of adrenergic receptor stimulation?
Α1 Smooth muscle contraction
Α2 Smooth muscle mixed effects, noradrenaline inhibition negative feedback, platelet activation.
Β1 Positive chronotropic, dromotropic and inotropic effects, increase rate of conduction and relaxation. Increased amylase secretion. Beta 1 also in kidneys, upregulates angiotensin
Β2 Smooth muscle relaxation (bronchodilation for example).
Β3 Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder.
How does B2 cause smooth muscle relaxation?
Gs activates adenylyl cyclase, catalyses formation of cAMP which activates PKA. PKA phosphorylates MLCK which means that it becomes inactive so cannot phosphorylate myosin to initiate contraction, therefore leading to muscle relaxation.
How does A1 lead to smooth muscle contraction?
Gq protein activates phospholipase C which changes PIP3 to be transformed into IP3 and DAG. IP3 diffuses into the cytosol and binds to the IP3 receptor on the endoplasmic reticulum / SR releasing intracellular calcium. Protein kinase C is activated and phosphorylates channels.
How do A2 receptors inhibit NA release?
Gi protein inactivates adenylyl cyclase decreasing the cAMP produces from ATP. Intracellular cAMP is decreased and PKA is not activated. Ca2+ channels not phosphorylated and less Ca2+ so noradrenaline inhibited.
How does B1 have positive inotropic and chronotropic effects?
Gs protein activates adenylyl cyclase which increases intracellular cAMP as more ATP converted, more PKA and more Ca2+ into the cells, more contraction. PKA phosphorylates phospholamban which normally inhibits SERCA, more Ca2+ enters SR for more contraction. If bound to by cAMP increasing open probability and increasing pacemaker rate. Gs directly opens L-type calcium channels.
What is an example of a B2 agonist, what is it used for?
Salbutamol, asthma
What are beta blockers?
B1/B2 antagonists
What is a selective B1 antagonist?
Atenolol
What is a non-selective B antagonist?
Propanolol
What is it a bad idea to give propanolol to an athsmatic?
Propenolol will also block the B2 receptors in the bronchioles and will stop the binding of noradrenaline meaning the airways will not relax and will be more restricted, inducing an asthma event
What are para co transmitters?
NO, VIP and ACh
What are symp co transmitters?
NA, ATP and neuropeptide Y
What is meant by cotransmission?
Release of several types of neurotransmitters from a single nerve terminal
Binding to receptors on the post synaptic membrane.
Upon nerve stimulation co transmitters are released at the same time as main transmitters
What are cotransmitters with ACh?
ATP and VIP
What are cotransmitters with NA?
ATP and dopamine
What are non adrenergic, non cholinergic transmitters?
Neuropeptides and NO
What is are examples of ATP receptor?
P2X, PY2
What does VIP do?
Cotransmitter for ACh, stimulates relaxation of smooth muscle in stomach, and dilation of coronary vessels
What does NPY do?
Binds to Y receptors (G protein) in the heart. They have a longer lasting effect than Nad on the effector cardiac cells
Where is NO released from?
Endothelial cells in blood vessels (EDRF)
What is NO synthesised from and by?
L-arginine by Nitric oxide synthases (eNOS)
What stimulates NO synthesis?
CalCaM
What is NO converted to?
sGC and cGMP
What does cGMP do?
cGMP is a secondary messenger that activates protein kinase G which inhibits Ca2+ channels leading to relaxation of smooth muscle.
What does sildenafil do?
Protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum.
Causes erection
Where are catecholamines synthesised?
In varicosity
