17_Synaptic Transmission 1_Q and A_Jonathan Flashcards Preview

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Flashcards in 17_Synaptic Transmission 1_Q and A_Jonathan Deck (43):
1

What are gap junction channels in the NS made of?

a connexon, is built from six identical subunits called connexins.

2

Are connexons pure gap junctions or can they be regulated?

Functionally, connexon permeability can be regulated by second messengers, pH and Ca2+. For example, Ca2+ “uncouple” electrically-coupled neurons by blocking connexons. This may prevent high concentrations of Ca2+ that arise as a given cell dies from traversing into coupled cells and promoting their demise.

3

Are mutations in connexins associated with any illnesses?

There are a number of central nervous system (CNS) diseases associated with genes encoding gap junction channel proteins. ex: congenital deafness.
Congenital deafness can be characterized as...
recessive,
nonsyndromic (restricted to the inner ear) deafness,
progressive dominant deafness,
syndromic (associated with other symptoms, especially skin diseases) deafness.
Mutations in specific connexin genes have been associated with all of these forms.

4

What is the significance of Connexin 26 in deafness?

mutations in the gene encoding connexin 26 are believed to account for ~50% of cases of inherited non-syndromic deafness.

5

What is the general mechanism involved in non-syndrome deafness and connexons?

Gap junctions expressed in the support cells of the Organ of Corti are involved in maintaining [K+] in the three chambers: The scala tympani and scala vestibuli have perilymph (ionic composition like CSF), and the scala media has endolymph (which has a high K+).
long-lasting changes in Vrest >> disruption of ionic homeostasis looses hair cells

Additionally, the loss of gap junction function compromises the passage of important signaling molecules, such as cAMP and IP3, which permeate Cx26-containing connexons (disruption of metabolic homeostasis). Disruption of both processes may contribute to the death of support cells and subsequent death of inner and/or outer hair cells.

6

What are the basics of chemical transmission of nerve cells?

1. Neurotransmitter is stored in presynaptic vesicles
2. Exocytosis of presynaptic vesicles requires influx of Ca2+ ions
upon depolarization
3. Specific cognate receptors for each neurotransmitter are
expressed in the postsynaptic membrane
4. Neurotransmitter release and opening of the postsynaptic
receptors is very fast: ~500 µsec from the time an action
potential invades the nerve terminal until current starts to
flow through the postsynaptic receptor (synaptic delay).
5. A variety of mechanism exists for terminating the action of
these substances.

7

What are the two classes of neurotransmitters based on size?

1. Small molecules:
Biogenic amines (dopamine, norepinephrine, epinephrine, 5-HT, histamine),
glutamate, γ-aminobutyric acid (GABA), glycine, and acetylcholine (ACh)

2. Larger and neurohormones
Over 100 identified, and list still expanding, For example, opioids, cannabinoids, substance P, vasopressin, oxytocin, gonadotropin releasing hormone (GnRH), neuropeptide Y, and many more.

8

What are the two major classes of neurotransmitter receptors based on function?

Ionotropic
Metabotropic

9

neurotransmitters in and of themselves are neither excitatory nor inhibitory. Rather it is the interaction of a given neurotransmitter with a specific partnering receptor that determines inhibition versus excitation.

Neurotransmitters in and of themselves are neither excitatory nor inhibitory. Rather it is the interaction of a given neurotransmitter with a specific partnering receptor that determines inhibition versus excitation.

10

What are excitatory neurotransmitters?

Nicotinic acetylcholine receptors
skeletal muscle ACh receptors
neuronal ACh receptors
Glutamate receptors
NMDA
AMPA
Kainate
5-HT3 class of serotonin receptors (a minor class of the serotonin receptors)
5-HT: 5-hydroxytryptamine or serotonin
Purinergic (adenosine and ATP) receptors

11

What are Inhibitory receptors (when activated by partnering ligand)

γ-Aminobutyric acid (GABA) type A receptors (also type C; not as prevalent). GABA interacting with GABAA receptors provides the major mechanism for generating fast inhibition (usually by hyperpolarization) in the adult brain. Early in development, GABA interacting with GABAA receptors depolarizes neurons. This is not due to any difference in the receptor itself or in GABA, but to a developmental shift in the intracellular concentration of [chloride], which is the major permeant ion through the GABAA receptor.

Glycine receptors. Glycine binding to glycine receptors also promotes fast inhibition. This type of receptor predominates in the spinal cord.

12

Sample list of Metabotropic Neurotransmitter Receptors (G Protein-Coupled):

α and β norepinephrine (NE) receptors
serotonin (5-HT1,2,4,5,6,7) receptors
dopamine (DA) receptors
muscarinic ACh receptors
GABAB receptors
L-AP4 glutamate receptors
ACPD (metabotropic) glutamate receptors
Cannabinoid receptors (CB1,2)
Well over 50 receptors for neuromodulatory peptides
ATP and adenosine

13

******The definition of excitation is that the action of the neurotransmitter is to drive the membrane potential (Vm) towards a value that is MORE DEPOLARIZED than the threshold potential for generating an action potential (Vthreshold) *********

******The definition of inhibition is that the action of the neurotransmitter KEEPS Vm from reaching Vthreshold*********

******The definition of excitation is that the action of the neurotransmitter is to drive the membrane potential (Vm) towards a value that is MORE DEPOLARIZED than the threshold potential for generating an action potential (Vthreshold) *********

******The definition of inhibition is that the action of the neurotransmitter KEEPS Vm from reaching Vthreshold*********

14

Just like ACh, which can activate both ionotropic (nicotinic) receptors and metabotropic (muscarinic) receptors, GABA, glutamate, serotonin, and ATP can also activate both ionotropic and metabotropic receptors. Release of a single neurotransmitter from a presynaptic axon terminal, therefore, can give rise to a multiplicity of postsynaptic effects that may vary in whether they promote excitation or inhibition in the target cell and in how long they last.

Just like ACh, which can activate both ionotropic (nicotinic) receptors and metabotropic (muscarinic) receptors, GABA, glutamate, serotonin, and ATP can also activate both ionotropic and metabotropic receptors. Release of a single neurotransmitter from a presynaptic axon terminal, therefore, can give rise to a multiplicity of postsynaptic effects that may vary in whether they promote excitation or inhibition in the target cell and in how long they last.

15

What is an Active Zone?

On the presynaptic side, the synaptic machinery is organized into structures called active zones.
ex: neurotransmitter plus vessicles, SNARES, Ca Dependent Channel

16

What are SNAREs on the pre-synaptic vesicles?
What are SNARES on the presynaptic membrane?

Vessicles:
1. Synaptotagmin
(Ca2+ sensor)
2. Synaptobrevin

Membrane
1. SNAP 25
2. Syntaxin

17

Explain SNARE fusion.

In brief, the two SNARE proteins in the plasma membrane (SNAP-25 and syntaxin 1) and the vesicle membrane SNARE (synaptobrevin) cycle through an assembly/disassembly cycle that requires energy provided by NSF (NSF is a membrane fusion protein aka an AAA + - ATPase). When these molecules come into contact with one another, they undergo a conformational change in which α-helices from the different molecules orient in parallel and “zipper” together (from the trans to the cis ends). This conformational zippering releases a large amount of energy, which, in turn feeds the fusion of the vesicle and presynaptic membranes.

18

What molecules help regulate SNARE fusion?

Muncs and Complexins

19

What are Muncs?
What are Complexins?

Small molecules called Muncs prepare the SNAREs for proper assembly, a molecule called complexin stabilizes or clamps the helices in a configuration that is then released to allow fusion when the molecule synaptotagmin binds calcium.

20

Explain the role of synaptotagmin as a Ca sensor in Ca dependent vessicle release?

Binding of calcium to the C2 domains of synaptotagmin also bestows a net positive charge to these regions and promotes their partial insertion into the negatively charged presynaptic membrane. Thus, synaptotagmin acts as the calcium sensor, relieves the clamp imposed by complexin and promotes the structural changes and release of energy that leads to membrane fusion and exocytosis of neurotransmitter.

21

How does disassembly work?

Finally, after fusion, NSF acts to promote disassembly of the complex, and the dissociation and retrieval of synaptobrevin.

22

What are chemical and natural exogenous inhibitors (neurotoxins) of SNAREs?

Botunilinum (BoTox) and Tetanus

23

How do BoTox and Tetanus work?

Both botulinum (BoTox) and tetanus toxins block exocytosis by proteolyzing SNARE proteins.

24

Which SNARE proteins are targeted by
Tetanus?
BoTox?

Synaptobrevin is cleaved by both tetanus toxin and BoTox.
Syntaxin and SNAP-25 are BoTox targets.

25

Wait a second, BoTox causes paralysis of muscles and Tetanus causes tetany. How does that work?

BoTox blocks synaptic transmission in motoneurons.
Tetanus toxins are retrogradely transmitted through the α-motoneurons that innervate muscle fibers and then retrogradely across the synapse from inhibitory interneurons. Thus, tetanus toxins target these secondary inhibitory interneurons neurons.

26

What are two factors that contribute to the "safety factor" at the neuromuscular junction?
(when a nerve fires, a muscle contracts)

1. Each action potential releases, on average, 300 vesicles of neurotransmitter (ACh)
2. As we shall discuss below, the postsynaptic fiber also has a highly specialized organization that optimizes the action of that large amount of neurotransmitter.

27

What is Lambert-Eaton Syndrome (LES)?

an autoimmune disorder in which antibodies are directed against the subset of presynaptic VDCC in presynaptic motoneurons and cholinergic neurons in the autonomic nervous system.

28

What is a treatment of Lambert-Eaton Syndrome LES?

Approximately 85% of LES patients respond favorably to the use of agents that inhibit potassium channels (e.g., 3,4-diaminopyridine).

29

Why does blocking K channels ameliorate LES?

K channels repolarize cells.
K blocker will prolong action potential >> increase depolarization >> and enhance

30

What increases efficiency on the the post synaptic side of neuromuscular junctions?

High density of ACh with ACh receptors
Note: there folds in the membrane that guide ACh to AChR. Interestingly, voltage-dependent Na channels are also close. AChesterase is also found here for quick removal of ACh.

31

What ions pass through the ACh-activated channel?

Both Na and K

32

If both Na and K pass through the ACh channel, how does it depolarize the cell?

Na is more permeable than K

33

What is the Reversible Potential?

Ex: in ACh-dependent ion channels, Na is more permeable than K and the cell has a net depolarization.
However, if the membrane depolarizes past the "reversible potential" the net ion flow would reverse.
Hence, in ACh-channels, there is no equilibrium potential, but there is a dynamic "reversible potential"

34

Important: The action of any neurotransmitter acting at its ionotropic receptor will be to drive the membrane potential of the postsynaptic cell towards the reversal potential for that receptor

The action of any neurotransmitter acting at its ionotropic receptor will be to drive the membrane potential of the postsynaptic cell towards the reversal potential for that receptor

35

How does neurotransmitter receptor desensitization work?

If a channel remains open for a long period of time (bound by an abundance of ligand), the channel will undergo conformational change in which it closes and is no longer stimulated by the neurotransmitter ligand.

36

Explain the mechanism and use of Succinylcholine.

Resistant to AChE is a serine hydrolase

Binds to ACh binding site with high affinity

Promotes AChR desensitization
and can be used to induce clinical paralysis
(e.g., myorelaxant for intubations)

effect is temporary due to half life

37

Explain the effects and mechanism of organophosphates.

used as insecticides and as weapons.
Inactivates AChE (esterase) leading to high levels of ACh which then desensitize the ACh channel

38

What is Myesthenia Gravis?

Antibodies attach ACh receptors >> injures receptors >> also the deep folds that trap ACh in the post synaptic membrane become less deep >> less ACh is trapped in the folds

39

What muscles are commonly effect by myasthenia gravis?

high repetitive use muscles, such as the eyelids

40

What is a Tx for myasthenia gravis?

mild and controlled use of AChE inhibitors

41

What is the Quantal Hypothesis?

Efficacy of synaptic transmission can be described by the quantal hypothesis:

m = n x p

m = mean quantal content i.e. the amount of neurotransmitter released
n = number of vesicles with a given amount of neurotransmitter in each
p = probability of release

42

How is the Quantal Hypothesis related to synapticplasticity?

Changes in the mean quantal content are an important component of synaptic plasticity (changes in m) that allows our brains to adapt to changes in our environment and optimize our behavioral outputs.

43

What is the m at the neuromuscular junction?
What is the m at any given central nerve?

Muscle: m = 300. One AP releases 300 vesicles, therefore muscle always fires
Central nerve = 0.5 one action potential releases 1 vesicle. Many other nerves are required to excite downstream pathways. This allows for highly adaptable synaptic plasticity.