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43 Cards in this Set

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RECAP: describe the structure of the ANS

•Projections from spinal cord to ganglia•Presynaptic cells release acetylcholine andactivate postsynaptic (postganglionic) cells. •Postganglionic cells form junctions withsmooth muscle cells, endocrine cells, cardiac cells, hepatocytesetc. etc.

•Projections from spinal cord to ganglia•Presynaptic cells release acetylcholine andactivate postsynaptic (postganglionic) cells. •Postganglionic cells form junctions withsmooth muscle cells, endocrine cells, cardiac cells, hepatocytesetc. etc.

Describe signal propagation in the ANS

•Fast electrical propagation along axons(action potentials) 
•Chemical transmission at synapses andterminals (neurotransmitter release) 
•These steps in the relay system can beblocked pharmacologically

•Fast electrical propagation along axons(action potentials)


•Chemical transmission at synapses andterminals (neurotransmitter release)


•These steps in the relay system can beblocked pharmacologically

What does excitability refer to?

“Excitability” refers to the ability todynamically alter the electrical potential (voltage) across the plasmamembrane.

How does a potential difference arise?

Any difference in the concentration of charged molecules

What is the resting membrane potential for cells?

-50 to -90 mV

What are ion channels?

•Membrane-spanning proteins that open aselective pore, allowing ion entry 


•Change cell excitability (mainly Na+ and K+) 


•Allow an influx of “signalling” ions – e.g. Ca2+

•Membrane-spanning proteins that open aselective pore, allowing ion entry




•Change cell excitability (mainly Na+ and K+)




•Allow an influx of “signalling” ions – e.g. Ca2+

What is meant by membrane depolarisation?

Inside the cell becomes more positive

What does membrane depolarisation cause?

Structural re-arrangements in the ion channel protein


Voltage gated potassium channel opens inresponse to depolarization

Structural re-arrangements in the ion channel protein




Voltage gated potassium channel opens inresponse to depolarization

What happens during action potential generation 1?

•Depolarization opensNa+  channels (fast)•Na+floods into the cell down its electrochemical gradient 
•This depolarizes the membrane even more (goes more positive)

•Depolarization opensNa+ channels (fast)•Na+floods into the cell down its electrochemical gradient


•This depolarizes the membrane even more (goes more positive)

What happens at action potential generation 2?

•K+ channels open(more slowly than Na+channels) 
•K+floods out of the cell down itselectrochemical gradient 
•Na+channels inactivatepreventing further depolarization 
•This repolarizesthe membrane

•K+ channels open(more slowly than Na+channels)


•K+floods out of the cell down itselectrochemical gradient


•Na+channels inactivatepreventing further depolarization


•This repolarizesthe membrane

What happens during action potential generation 3?

•K+ channels inactivate. 
•Ion pumps and transporters use energyfrom ATP or counter-transport to re-establish resting membrane conditions

•K+ channels inactivate.


•Ion pumps and transporters use energyfrom ATP or counter-transport to re-establish resting membrane conditions

What does a graph of the changing membrane potentials look like?

What is saltatory conductance?
•Mechanism for increasing speed andreliability of conduction 
•Glial cells coat axons in insulatingmyelin sheets
•Ion channels are clustered at unmyelinated“Nodes of Ranvier”
•Action potential “jumps” between nodes

•Mechanism for increasing speed andreliability of conduction


•Glial cells coat axons in insulatingmyelin sheets


•Ion channels are clustered at unmyelinated“Nodes of Ranvier”


•Action potential “jumps” between nodes

What happens when the action potential reaches the synapse or terminal?
Once the action potential reaches asynapse (neuron to neuron junction in the ganglion) or terminals to other celltypes (e.g. smooth muscle, endocrine cells), chemical transmitter is released.

Once the action potential reaches asynapse (neuron to neuron junction in the ganglion) or terminals to other celltypes (e.g. smooth muscle, endocrine cells), chemical transmitter is released.

How are transmitters synthesised and stored?
•Synthetic enzymes make transmitter fromprecursors
•Transmitter is transported into vesiclesin the presynapticnerve terminal 


Synthetic enzymes generate NT frominactive precursors. Vesicular transporters use activetransport to concentrate NT...

•Synthetic enzymes make transmitter fromprecursors


•Transmitter is transported into vesiclesin the presynapticnerve terminal




Synthetic enzymes generate NT frominactive precursors. Vesicular transporters use activetransport to concentrate NT within the vesicle.

How are vesicles released?
•An incoming action potential depolarizesthe terminal
•Voltage-gated calcium channels open
•Calcium triggers vesicle fusion andtransmitter release

•An incoming action potential depolarizesthe terminal


•Voltage-gated calcium channels open


•Calcium triggers vesicle fusion andtransmitter release

How are the postsynaptic receptors activated?

•Receptors for the transmitter on thepostsynaptic cell are activated. 
•Ligand-gated ion channels open.

•Receptors for the transmitter on thepostsynaptic cell are activated.


•Ligand-gated ion channels open.

What opens ligand-gated ion channels?

•Binding of an agonist to the receptoropens an ion channel 
•This depolarizes the postsynaptic cell


e.g Nicotinic acetylcholine receptornAChROpen pore lets Na+ and K+ (andsome Ca2+ ) ions through.

•Binding of an agonist to the receptoropens an ion channel


•This depolarizes the postsynaptic cell




e.g Nicotinic acetylcholine receptornAChROpen pore lets Na+ and K+ (andsome Ca2+ ) ions through.

How are NT's cleared from the intermembrane space?

•The synaptic “signal” must be turned off
•Enzymatic degradation or active uptake oftransmitter eliminates it from the extracellular space

•The synaptic “signal” must be turned off


•Enzymatic degradation or active uptake oftransmitter eliminates it from the extracellular space

What happens when the NT reaches the target cell (terminal cell)?

•Boutons to smooth muscle, endocrine cellsetc. activate G protein coupled receptors (GPCRs)•Activation or inhibition of secondmessenger pathways

•Boutons to smooth muscle, endocrine cellsetc. activate G protein coupled receptors (GPCRs)•Activation or inhibition of secondmessenger pathways

What happens for sympathetic innervation (stimulation)?

•Noradrenalineacts on alpha and beta adrenoceptors 
•a and b receptors have variable effectsdepending on cell type

•Noradrenalineacts on alpha and beta adrenoceptors


•a and b receptors have variable effectsdepending on cell type



What happens for parasympathetic innervation?

•Acetylcholineacts on muscarinic(M) receptors 
•M1,M2 and M3 receptors have variable effects depending on cell type

•Acetylcholineacts on muscarinic(M) receptors


•M1,M2 and M3 receptors have variable effects depending on cell type

RECAP: Describe synaptic transmission

•Incoming action potential triggers
vesicle fusion
•Activation of postsynaptic receptors
propagates AP 
•Clearance terminates signal

•Incoming action potential triggersvesicle fusion


•Activation of postsynaptic receptorspropagates AP


•Clearance terminates signal

What would blocking the voltage gated Na+ channels do?

Prevent excitation of both pre-and postsynaptic cells

What are some drugs which block the Na+ channels?

–Lidocaine (local anaesthetic)


–Lamotrigine(antiepileptic)

What does lidocaine do?

Blocks the pore of the Na+ channel after opening, preventing
passage of ions 

Blocks the pore of the Na+ channel after opening, preventingpassage of ions

How can you interfere with NT synthesis?

A false substrate competes for enzymecatalytic site




Build up of inert product anddepletion of transmitter

What is a drug which inhibits the synthetic enzymes?

Methyl-DOPA
is a false substrate for DOPA decarboxylase. Methyl-dopamine
cannot be converted to noradrenaline

Methyl-DOPAis a false substrate for DOPA decarboxylase. Methyl-dopaminecannot be converted to noradrenaline

What does L-DOPA do?

L-Dopa is the precursor to dopamine, it is used to increase dopamine concentration. It can be used as a therapy in Parkinson's disease

What does interference with vesicle loading do?
Vesicles fail to load 

Stores depleted by on-going
activity

Vesicles fail to load




Stores depleted by on-goingactivity

What is an example of a drug which interferes with vesicle loading?

Reserpineblocks NA uptake (and other monoamines)

What are some drugs which interfere with vesicle release?

•Calcium triggers vesicle fusion andtransmitter release


- Conotoxin blocks calcium channels


- Botulinumtoxin (Botox)degrades vesicle release machinery

What do antagonists of ionotropic receptors (ligand gated ion channel) do?

Antagonists of ionotropic
receptors prevent depolarization of the postsynaptic cell

Several mechanisms: occupy
NT binding site, prevent channel opening,
or block the open pore      

Antagonists of ionotropicreceptors prevent depolarization of the postsynaptic cell




Several mechanisms: occupyNT binding site, prevent channel opening,or block the open pore

What do antagonists of metabotropic receptors do?

•Antagonists of metabotropic
receptors prevent target cells from responding to released NT

•Occupy binding site (red) or
inhibit G protein (green)

•Antagonists of metabotropicreceptors prevent target cells from responding to released NT•Occupy binding site (red) orinhibit G protein (green)

Examples of antagonists

–Tropicamide (mAChRblocker)


–Atenolol (bR blocker)


–Tamsulosin (aR blocker)

Examples of agonists

–Salbutamol (bR agonist)


–Pilocarpine (mAChRagonist)


–Nicotine(nAChRagonist)

What does inhibition of transporters or degradation of enzymes do?

Inhibition of transporters or degradationenzymes prolongs activation of post synaptic cell

Name some drugs which inhibit the clearance of transmitters

- Amitriptyline
inhibits NA uptake (blue)
- Neostigmine
blocks acetylcholinesterase (red)

- Amitriptylineinhibits NA uptake (blue)


- Neostigmineblocks acetylcholinesterase (red)

Examples of B-blockers (antagonists), their indictations, contra-indications, and side effects

•Atenolol, propranolol,acebutolol




•Indications:


–Hypertension,angina, arrythmias




•Contra-indications:


–Asthma,bradycardia,severe peripheral arterial disease, etc.




•Side effects:


–Bronchospasm, GIdisturbances, hypotension, bradycardia, visual disturbances, headache,dizziness, etc. etc.

What is the B-blocked mechanism of action?

•Counteracts sympathetic input 
•Reduce cardiac output 
•Risk of pulmonary side effects

•Counteracts sympathetic input


•Reduce cardiac output


•Risk of pulmonary side effects

Examples of B-blockers (anti-muscarinics), their indications, contra-indications, and side effects

•Muscarinic acetylcholine receptor antagonists:


•Hyoscine, atropine, oxybutynin




•Indications


–Premedicants todry bronchial and salivary secretions (during surgery), bradycardia, GIdisorders, urinary incontinence, cycloplegia




•Contra-indications


–Glaucoma,myasthenia gravis, urinary retention




•Side effects


–Drymouth, blurred vision, constipation, tachycardia, palpitation, arrythmias

What is the antimuscarinic mechanism of action?

•Counteracts parasympathetic input
•Inhibits glandular secretion
•Blocks smooth muscle contraction

•Counteracts parasympathetic input


•Inhibits glandular secretion


•Blocks smooth muscle contraction

What are clinical signs of poisoning or defects in autonomic control?

•Pupil dilation


–Mydriasis(pupil dilation)


–Miosis(pupil constriction)


–Lightreflex




•Heart beat rate


–Bradycardia(decreased rate)


–Tachycardia(increased rate)




•Sweating/salivary outflow


–Profusesweating


–Drymouth