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BioMed 2 > Chemical Synaptic Transmission > Flashcards

Chemical Synaptic Transmission Flashcards

1
Q

What is the criteria for defining a neurotransmittter?

A
  1. It must be present at the synapse (along with appropriate synthetic pathways).
  2. It must be released in response to appropriate stimuli (pre-synaptic action potentials) through a Ca2+ dependent mechanism.
  3. Specific post-synaptic receptors must be present (agonists and antagonists have the same actions on the
    post-synaptic effects of synaptically released and exogenously applied transmitter).
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2
Q

What is the neuromuscular junction (NMJ)?

aka motor endplate

A

The synapse between motorneurone and skeletal muscle

called motor endplate because the motorneurone terminal branches and makes several connections w muscle fibre

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3
Q

How is ACh made and where is it made and how is it transported?

A

Synthesied in the PNS nerve terminal from choline and acetyl CoA by choline acetyltransferase (ChAT)
Transported into vesicles by vesicular transport (high H+ concentration inside vesicle, transporter exchanging H+ for ACh)

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4
Q

Whats vesamicol?

A

Inhibits vesicular acetylcholine transporter
(VAChT) which loads ACh into vesicles

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5
Q

Whats immunocytochemistry?

A

Technique that uses antibodies raised against ChAT, then labels them with secondary antibody conjugated with a marker against primary antibody?

This allows microscopic identification of the location of ChAT-containing (cholinergic) neurones

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6
Q

What is end-plate potential (EPP)?

A

Voltage that depolarizes in the muscle fibres after motorneurone stimulation

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7
Q

How is Ca released? How does it promote contraction?

A

Action potential depolarizes muscle fibres, which depolarizes t-tubule, which triggers Ca release from sarcoplasmic reticulum via ryanodine receptor type 1, which interacts with troponin and stimulates muscle contraction

DHP receptors undergo conformational change during AP, and this interacts with ryanodine receptor to release Ca

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8
Q

What is different in cardiac muscle regarding Ca release?

A

Ca is released through L-type channel (DHP-receptor) FIRST to activate ryanodine receptors

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9
Q

What is tetrodoxin (TTX)?

A

It blocks voltage-gated Na+ channels in the motorneurone, which stops pre-synaptic action potential and the EPP

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10
Q

What is the safety factor?

A

Refers to the margin that an EPP exceeds AP threshold
Means that a single AP will ALWAYS trigger the release of enough ACh to elicit a post-junctional action potential and muscle contraction

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11
Q

What relationship does Ca have with ACh release?

A

Ca2+ entry triggers the exocytosis of vesicles releasing ACh into the synaptic cleft

No calcium = no transmitter release= no response

Blocking voltage-gated Ca2+ channels abolishes the post-synaptic potential (as does removing external Ca2+

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12
Q

What is quantal theory?

A

When EPP is reduced, motor neuronal stimulation elicits mini EPPs, caused by Ca vesicles (‘quanta’) releasing Ca into the synapse asynchronously

EPP is caused by hundreds of quanta releasing at the same time

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13
Q

How are neurotransmitters released via : Ca2+ -induced vesicular exocytosis?

A

Synaptobrevin interacts with SNAP-25 and syntaxin and draws the two membranes together. Ca binds to synaptotagmin and then interacts with the rest of the proteins and fuses the vesicle to the membrane

SNARE complexes form to intitally bring the two membranes together
SNAP-25 and syntaxin are on the synapse, and synaptobrevin is on the vesicle

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14
Q

What do botulinum toxins do?

A

Botulinum toxins are peptidases,specifically taken up by motoneurones, that cleave SNARE proteins preventing exocytosis / ACh release causing paralysis

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15
Q

What functions do clatherin and dynamin have in vesicle endocytosis?

A

Clathrin attaches to the membrane with the help of adapter proteins. As it polymerizes it causes curvature of the membrane. Ultimately a vesicle is cleaved off with the help of dynamin.

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16
Q

What is the function of Nicotinic Acetylcholine Receptors (nAChR)?

nicotine is a selective agonist that can bind with high affinity to the ACh binding site of these receptors
nAChR belong to the ligand-gated ion channel super-family.

A

At the NMJ, ACh binds nAChRs
nAChRs mediate the EPP

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17
Q

What is the End Plate Current (EPC?) What is reversal potential?

A

EPC is the current flow resulting from nAChR activation
Reversal potential (E.ACh) is the potential at which no EPC is observed
- E.ACh changes in the depolarizing direction if we increase extracellular K+
- E.ACh changes in the hyperpolarizing direction if we reduce extracellular Na+

because the normal resting potential is closer to EK+, it is predominantly Na+
flux that mediates the EPP.

18
Q

What does acetylcholinesterase (AChE) do?

A

Hydrolyses ACh to choline and acetate
Important because it stops ACh from signalling

19
Q

What does hemicholinium do?

A

Blocks high-affinity choline transporter (ChT), which carries choline into acetylcholine-synthesising neurons
## Footnote

Choline transporter is A high affinity transporter, that co-transports Na+, moves choline back into the motoneurone terminal, plays important role in re-cycling choline ready for new ACh synthesis

20
Q

What do non-polarizing blockers do? Give two examples

A
  • they are competitive, reversible, receptor antagonists, compete for binding site on nAChR
  • Can be overcome by increased ACh conc (via anti-cholinesterase drugs)
  • eg. tubocurarine and atracurium

Non-depolarizing blockers compete with ACh for the agonist binding site on the nAChR i.e. they are competitive, reversible, receptor antagonists. A key feature of the actions of non-depolarizing blockers is that they can be overcome by increasing the ACh concentration in the synaptic cleft. This can be achieved by administering an anti-cholinesterase drug.
Blocking AChE prevents ACh breakdown thereby increases ACh concentration at the NMJ. This increases the probability that a molecule of ACh will occupy the binding site on the receptor rather than a molecule of antagonist.

21
Q

What do depolarizing drugs do? Give an example

A
  • initially activate the nAChR, but ultimately causes a loss of electrical excitability at the NMJ
  • Cannot be releived by anti-cholinesterases
  • Suxamethonium (succinylcholine)

The sustained depolarization of the NMJ by suxamethonium leads to prolonged voltage-gated Na+ channel inactivation. Thus, an initial action potential is elicited in the muscle by the depolarization but subsequent action potentials cannot be produced because voltage-gated Na+ channels cannot recover from inactivation until the membrane potential has returned to its resting level. In addition, the prolonged presence of agonist leads to changes in nAChR conformation resulting in a receptor that does not respond to agonist. This is known as receptor desensitization

22
Q

What does a-bungarotoxin do?

A

highly potent, selective and irreversible peptide inhibitor of muscle nAChR that also binds to the ACh binding site

Use of this toxin was instrumental in allowing sufficient receptor protein to be purified to enable the initial structural characterization of the muscle nAChR. We also saw the use of fluorescently labelled aBGTx to demonstrate the location of nAChR at the NMJ in the Chemical Synaptic Transmission 1 lecture.

23
Q

Which is faster, GPCRs or ligand gated ion channels?

A

The ion channels are significantly faster.

Depending on the complexity of the signaling pathway the time course of the effects of GPCR activation can range from 100’s of milliseconds to seconds

24
Q

What are the three GPCR groups?

A

A: Largest group, amine transmitters, peptides, purines, cannabinoids. Short extracellular N–terminus.
Ligand binds to TM helices (amines) / or extracellular loops (peptides)
B: Intermediate length extracellular N–terminus. N-terminus incorporates Ligand Binding Domain
(LBD).
C: metabotropic glutamate receptors, GABAB, Ca2+
-sensing receptors. Long extracellular N–terminus.
LBD in long N-terminus – (“Venus Fly Trap” domain).

25
Q

Which GPCR terminus is extracellular, C or N?

A

N terminus is extracellular
C terminus is intracellular

26
Q

What are the properties of muscarinic ACh receptors M1, M2, and M3?

mAChRs are a kind of GPCR

A

M1: found in neurones and mediate a slow EPSP in ganglia
M2: found in the heart; their activation results in a decrease in the rate and force of contraction
M3: mediate secretion, contraction of visceral smooth muscle, and in some cases relaxation of vascular smooth muscle

Muscarinic M1 receptors have been demonstrated to mediate slow excitatory transmission at central synapses through the closure of K+ channels.

27
Q

What are the four effects of muscarinic ACh receptors?

A
  1. activate phospholipase C to cause the production of IP3 and diacyl glycerol
  2. inhibit adenylate cyclase causing a decrease in the levels of cAMP
  3. directly activate K+ channels
  4. directly inhibit Ca2+ channels
28
Q

What role do muscarinic receptors and ACh have in cardiac action potential?

GPCR, ACh

A
  • Muscarnic receptors slow heart rate and reduce force of atrial contraction
  • Stimulating vagus nerve leads to ACh release, which activates M2 mAChRs
  • This activates G protein which opens K channels which 1. shortens cardiac AP & 2. hyperpolarizes membrane (inc interval btw APs)

Heart -> acetylcholine-> M2-> Rate drops

Both mechanisms (1 and 2) contribute to the bradycardic (slowing) effects
K+ channel opening is the result of By (beta gamma) subunits of the activated G protein binding directly to the channel, i.e. no diffusible second messenger is generated.
It is also likely that the reduction in force of contraction is a result of the By subunits of the activated G protein binding directly to voltage-gated Ca2+ channels and inhibiting their opening. This will reduce Ca2+ entry into the cardiac muscle during the cardiac action potential and, therefore, reduce the contractile force.

29
Q

How do M3 muscarinic receptors mediate smooth muscle contraction?

A
  • Second messengers (IP3 and DAG) generated by the hydrolysis of phosphatidylinositol 4,5 bisphosphate (PIP2).
  • inositol trisphosphate IP3 releases Ca2+ from intracellular stores
  • diacylglycerol (DAG) which stimulates Protein Kinase C (PKC).

GPCRs coupled to Gaq, stimulate phospholipase C to hydrolyse PIP2 producing two second messengers
PKC mediates phosphorylation of various enzymes

30
Q

Whats the relationship between GPCRs and cAMP and PKA?

A
  • Gas stimulates adenylyl cyclase which produces cAMP
  • cAMP usually stimulates enzyme protein kinase A
  • Gai can inhibit adenylyl cyclase

Gas= G-alpha.s, Gai= G-alpha.i

31
Q

What is the role of GPCRs in slow synaptic transmission in CNS?

A
  • GBy subunit-mediated opening of K+ channels causes slow inhibitory synaptic transmission seen at synapses
  • 5-HT acting through 5-HT1A receptors mediates inhibitory synaptic potentials that have time courses of greater than 1 second
32
Q

Which types of muscle are striated?

A
  • Skeletal and cardiac

skeletal= 40% of body mass

smooth muscle is not striated

33
Q

What is a fascicle?

A
  • composed of multiple muscle fibres that forms a single unit of contraction
  • recieves input from singluar motor neuron,
  • Is surrounded by connective tissue

muscle fibres are single cells that are multinucleated

34
Q

What are myofibrils and what are they composed of?

A
  • Filaments that run along the axis of muscle fibres
  • Thin filaments: f-actin (helical like twisted rope)
  • Thick filaments: myosin (Have head and tails, heads interact w actin)
  • Z-disk: anchor point for thin filaments
  • M line: anchor point for thick filaments
  • Sarcomere: unit of Z to Z

Thin filaments are composed of globular-actin that has aggregated into two helical filaments of f-actin
Length of filaments do NOT change, they simply overlap during contraction and sarcomere length changes

35
Q

Why are myofibrils surrounded by sarcoplasmic reticulum and t-tubules?

A

SR is a membrane that stores Ca2+ (only intracellular)
T-tubules are important in AP and Ca2+ release (extra and intra cellular)
Release of Ca2+ is what triggers myofibril contraction

36
Q

What does Ca-ATPase/SERCA do?

SERCA= sarcoplasmic endoplasmic reticulum calcium ATPase

A
  • Terminates Ca release by re-uptake into the SR
  • Two Ca2+ ions are transported for every molecule of ATP hydrolysed but this also involves the movement of two H+ from the SR to the myoplasm
37
Q

What does tropoamyosin do?

A

It prevents myosin from interacting with actin at rest

38
Q

What does Troponin C do?

A

Ca released by SR binds troponin C which moves tropoamyosin out of the way so myosin can bind actin

39
Q

How does myosin use ATP and Ca to move along actin?

A
  • In a relaxed state, ATP is partially hydroylsed (ADP & Pi) on myosin and myosin is at 90˚ to actin
  • Once bound to myosin (ADP and Pi released) angle becomes 45˚ and pulls actin 10nm towards the M-line
  • If Ca2+ is still present at concentrations greater than 0.1 microm, myosin-actin interactions keep happening.
  • If the Ca2+ concentration has fallen below this level tropomyosin will move back to block the myosin/actin binding site and the muscle will relax
40
Q

What is the force-velocity relationship?

A
  • Tension produced proportional to number of myosin heads interacting with actin
  • Speed at which sarcomere changes length is related to the force of the load you put on it
    ○ Light load= shorten quick
    ○ Heavy load= shorten slower
    ○ Max load= sarcomere wont shorten at all
  • maximal power occurs at sub-maximal load - around one third of maximum load (force).

Muscle can lift heavy objects slowly, but move light loads quickly Depends on number of sarcomeres and cycle time for filament interaction

41
Q

What are three things that can vary muscle force?

A
  1. Changing number of units activated
  2. Changing frequency of activation
  3. Changing muscle length

BioMed 2 (16 decks)

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