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Membrane Excitability > PRINCEEEEEY > Flashcards

PRINCEEEEEY Flashcards

1
Q

what does cholinergic mean?

A

via Ach

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2
Q

structure of Ach?

A

Ch3-C=O-O-CH2-N+ x3 CH3
draw out

permanent positive charge on N

ester link where Ach is cleaved to activate it.

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3
Q

general cholinergic transmission?

A

voltage sensitive calcium channels
Ca enters
Ach vesicles fuse
bind to ACh receptors on target organ

ACh esterase break down into acetate and choline

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4
Q

how is choline recycled?

A

choline acetyl transferase

choline - ACh
AcetylCoA - CoA

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5
Q

nicotinic/muscarinic receptors?

A 
Muscarinic - GPCR, slow
monomeric
M1-5 subtypes
1ACh site
agonists: muscarine, pilocarpine
antagonists: atropine, hyoscine
Nicotinic - ligand gated, fast
pentameric
18 subunits
2ACh sites
agonists: nicotine, suxamethonium
antagonists: atracurium, tubocurarine, bungarotoxin
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6
Q

antagonists of NMJ?

A

conotoxin M1
cobratoxin

bind to same site as ACh extremely tightly.
not really competitive antagonist.

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7
Q

describe competitive antagonists at nAChRs

A

flacid paralysis.
block site of ACh, no Ca influx

can reverse by increasing conc of ACh

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8
Q

describe agonists at nAChR

A

depolarising blocker.

muscle twitching followed by flacid paralysis.

sustained depolarisation followed by decreased electrical sensitivity/desensitization.
can bind but won’t open channels.

can’t be reversed with AChE inhibitors.

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9
Q

applications of NMJ blockers?

A

muscle relaxation during surgery.

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10
Q

name drugs which block NMJ

A

non depolarizing competitive blockers:
atracurium
pancuronium

tubocurarine - african hunting, bad effects on autonomic system

dopolarising blockers:
suxamethonium

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11
Q

pharmacokinetics of blockers on NMJ?

A

Intravenous - rapid (30 sec onset)

Suxamethonium - hydrolysed by serum Cholinesterase (fast recovery - 3 min). dangerous if low s ChE

Atracurium - breaks down spontaneously, very safe.

Pancuronium – much longer duration of action (100 -200 minutes). Used in euthanasia, executions.

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12
Q

what receptors are responsible for nicotine addiction?

A

receptor containing 2 x a4 and 3 x B2 in a pentomer.

present in CNS.

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13
Q

treatment for nicotine addiction?

A

varenicline (champix) = partial agonist at a4B2 receptor.

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14
Q

describe botulinum toxin

A

Active principle in botulism food poisoning, lethal dose in mice = 1 trillionth of a gram!

Blocks release of ACh by breaking down SNARE proteins

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15
Q

effects of botulinum toxin?

A

Paralysis of skeletal muscle, autonomic block,
systemic effects = death

Can be used to paralyze muscles on local/small basis,
can treat muscle spasms, wrinkle removal

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16
Q

describe inhibitors of Acetylcholinesterase.

A

stop breakdown on ACh.

prevents termination of signalling.

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17
Q

name irreversible inhibitors of AChE

A

Nerve gases and insecticides e.g. sarin, VX covalently modify AChE

Causes muscle paralysis and over activation of autonomic nervous system (esp parasympathetic)

Atropine counters some symptoms on heart rate/bp (via mAChR). doesn’t help muscle paralysis

Pralidoxime regenerates enzyme if administered within five hours.

18
Q

reversible inhibitors of Acetylcholinesterase

A

Competitive (edrophonium, physostigmine, neostigmine, rivastigmine)

Non-competitive (tacrine, donepezil)

Used in situations where there is a need to “Boost” cholinergic transmission.

19
Q

Uses of reversible Acetylcholinesterase inhibitors

A

Reversal of non-depolarizing NMJ blocker e.g. pancuronium

Autoimmune myasthenia gravis:
immune attack on nAChR in NMJ. Increasing ACh boosts transmission via remaining receptors.
increases muscle strength.
edrophonium (test); pyridostigmine, neostigmine, physostigmine

Alzheimer’s disease:
loss of cholinergic neurons.
tacrine, donepezil

20
Q

what is the safety margin of end plate potential?

A

high SM of EPP means large safety net, ie too many receptors/ACh to ensure all goes to plan

21
Q

what is myasthenia?

A

muscle weakness, comes about when safety margin is compromised.

22
Q

describe myasthenia gravis

A 
“Severe Muscle Weakness”
 Drooping eyelids, double vision
 Impaired speech
 Limb, trunk muscles
 Respiration
 Incidence: 1:10000

can’t fire AP as easily, less muscle contraction thus weakness.
breathing problems since diaphragm is skeletal muscle.

23
Q

why does myasthenia gravis occur?

A

autoimmune disorder, attack on nAChR on muscle membrane

Internalisation - antibodies bind to nAChR, less AChR present

Immune attack - end plate damage

Denatured a subunit is antigenic

Most antibodies compete with one another

Main Antigenic Region (MIR) -amino acids 67-76
67-76 on extracellular loop of a subunit, exposed.

24
Q

describe the membrane with myasthenia gravis

A

fewer nAChRs.

changed shaped of membrane,??

25
Q

treatment of myasthenia gravis?

A

Thymectomy, taking thymus out. remission in 70%, we dunno y lol.

Immunosuppression, open to immune attacks

Plasma exchange with donor, contains antibodies, only temporary??

Cholinesterase inhibitors, increases conc of ACh in synaptic cleft. good stuff.

Anti-idiotype antibodies
antibodies to the antibodies, future therapy.

26
Q

describe Lambert Eaton Myasthenic Syndrome.

why is it’s diagnosis good?

A

auto immune attack on voltage sensitive calcium channels on pre synaptic membrane.

paraneoplastic disorder - 60% of people with LEMS have lung cancer.
can see LEMS symptoms before cancer symptoms.

27
Q

compare LEMS to MG.

A

MG:
eyes first, neck/swallowing
arms and legs later on

LEMS:
legs –> arms –> eyes

28
Q

what happens to babies born to mothers with MG?

A

have a form of MG, not auto immune only temporary.
mothers antibodies passed through placenta.
once those antibodies passed through the body the baby will recover.

29
Q

describe Congenital Myasthenic Syndromes

A

Diverse inherited disorders Autosomal dominant, recessive
Synaptic, pre- or post-synaptic mechanisms

Pre-synaptic:
Decrease in synaptic vesicles
Decrease in ACh synthesis/packaging
(decreased release of ACh)

Synaptic:
Decrease acetylcholine esterase
(cation overload, depolarising block)

Post-synaptic:
Mutations in AChR subunit genes

30
Q

what are Slow Channel Myasthenic Syndromes?

A

simplified end plate.
decreased AChR.
widened synapse/ as in bigger gap between pre/post.

31
Q

open/closed states or summin

A

wut

32
Q

how many ACh receptors does a nAChR have?

A

2, on each a subunit.

33
Q

dem graph things rates idk wut

A

butt

Values of rate constants determines distribution openings and closings

34
Q

slow channel syndrome alpha G153S?

A

glycine to syrine
opens too frequently

dissociation rate constant for ACh decreased from 17000 to 1000.

rate at which channel closes (a) decreases from 2300 to 900.

slowing of channel closing and slowing of ACh dissociation over stimulates the receptor.

35
Q

slow channel syndrome alpha V249F?

A

valine to phenylalamine.
249 just below the channel gate, in the M2 (2nd TMD)

opening time increases
closing time decreases
dissociation rates decrease

36
Q

rate constants n that?
B
a
k-1 k-2

A

B opening time of channel
a closing time of channel
k-1 dissociation rate of first ACh

37
Q

describe all slow channel MS

A

SCMS

aN217K, eT264P, b266M + others

Dominant - cation overload (depol. block)

Variable clinically, M2 > M1 > EC domain

Treatment???
reduce receptor function

38
Q

what happens if you give somebody with SCMS AChE inhibitors?

A

even more channel activation, nonono.

39
Q

describe P121L fast channel MS

A

prolene to lucine

Severe myasthenic symptoms
Normal endplate structure
Normal number AChR

B decreases, opening rate decreases and rarely opens.

Autosomal recessive.

Patients have two e subunit mutations
eG-8R signal peptide
eS143L deletion of glycosylation site

Respond to AChE inhibitors (incompletely)

40
Q

what is a mode switch mutation?

A

(only seen in lab)

Insertion in cytoplasmic loop of epsilon
Reduced expression of epsilon

Compensatory expression of foetal gamma subunit instead, which doesn’t work as well.

Entire kinetic scheme disrupted in lab, not in patient since expression levels are too low.

41
Q

startle syndrome?

A

ligand gated ion channel channelopathy.

mutation in glycine receptor, inhibitory NTR in spinal cord.

42
Q

epilepsies?

A

mutation in GABA A or neuronal nicotinic receptors.

Membrane Excitability (7 decks)

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