Neurotransmitters 1 Flashcards by Sara Kayeum

Fast, reliable, and bidirectional mode of communication throughout the CNS

Electrical synapses/gap junctions

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Electrical synapses/gap junctions allow what type of molecules to pass from one cell into another? What type of passage?

Ions and small molecules (<1000 Da); Diffusion

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What proteins form the electrical synapse/gap junction? Be specific in the makeup.

Connexins, ~20 of them
6 connexins form 1 connexon
2 connexons align to form a channel

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What are electrical synapses important in? List 4.

Embryonic stem cells
Retina
Auditory system
Cortex

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What regulates an electrical synapse? List 4.

Cytosolic pH
Cytosolic calcium
Phosphorylation
Voltage

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This is caused by mutations in one connexin

The most common form of inherited deafness in Caucasian populations (DFNB1)

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What do electrical synapses allow?

Allow groups of similar neurons to be synchronized e.g. hormone-secreting neurons in hypothalamus - get burst of hormone secretion; neocortical interneurons; cells of adrenal medulla

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Explain the membrane potentials in pre and post-synaptic neurons

Potential in downstream neuron won’t go as high
Signal will be degraded
Signal is less intense, more spread out
Not faithfully transmitter. Quick, but can’t keep doing this forever

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Do electrical synapses have a synaptic delay?

Yes, ~0,1 msec

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What is the predominant mode of signaling?

Chemical synapses

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Which type of synapse (electrical or chemical) is faster?

Electrical synapses. (Chemical are not quite as fast)

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2 key features of a chemical synapse

Synaptic vesicles

2. Receptors on post-synaptic ending

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What is the major different in contact of pre and post synaptic membranes in chemical and electrical synapses?

Electrical synapse-connected by desmosomes, no synaptic cleft, touching each other
Chemical synapse-no direct contact with each other, 2-4x bigger membrane space, contain synaptic cleft ~20 nm

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In vesicular release for major neurotransmitters, an action potential propagates down an axon and does what to the presynaptic terminal?

Depolarizes it

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What is the consequence of depolarization of the presynaptic terminal in vesicular release?

Opens voltage gated Ca2+ channels

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What is the difference in intracellular and extracellular concentration of Ca2+ ?

[Ca2+] outside = mM (10^-3)
[Ca2+] inside = uM (10^-6)

much smaller inside

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What initiates fusion of synaptic vesicles with plasm membrane in vesicular release?

Influx of Ca2+. After depolarization, calcium voltage gated channels open and calcium ions enter down their electrochemical gradient. (Equilibrium potential for Ca = ~100 mV)

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After fusion of synaptic vesicles with plasma membrane, vesicle content is released into this very small region

Synaptic cleft

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What type of receptors on post-synaptic cells do released transmitters act on?

Ligand gated ion channels or receptors that use G proteins (GPCRs)

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True or false: Transmitters can only act on receptors on the post-synaptic cell

FALSE. They can also act on receptors on the pre-synaptic terminal

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What inactivates transmitter? List 4.

Na+ dependent reuptake, degradation and/or diffusion, or glial metabolism

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Vesicular membrane must be retrieved. What two events facilitate this?

Exocytosis followed by endocytosis

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Pre-synaptic vesicles contain more than one kind of vesicle. Release from these types has a different Ca2+ dependence and occurs at a different place

Large dense core vesicles (LDCVs)

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Calcium is a crucial player of vesicle release. What are two of its sources?

Usually comes across the synaptic plasma membrane to start release
Can also be liberated from intracellular space

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3 benefits of chemical synapses

1. Amplification of signal 2. Integration of inputs 3. Makes use of different receptors

How do different receptors create a variety of post-synaptic effects?

Ligand gated ion channel-response is RAPID Other receptors link to signaling pathways that alter morphology, receptor localization, gene transcription- response is SLOWER

Major mode of release

Vesicular release

Most prevalent vesicle, lined up at synapse

Small clear synaptic vesicles (SSVs)

These vesicles are less numerous and not as localized

Large dense core vesicles (LDCVs)

What type of chemical mediators are released by diffusion (non vesicular release)

Lipid mediators like anandamide/endocannabinoids, neurosteroids, and gasses like NO

What type of chemical mediators are released by transport?

Hydrophilic molecules (via carriers or pores)

There are over a hundred different neurotransmitters known. They are split into what two groups?

Smal molecules and peptides

List 5 biogenic amines that fall under small molecules group of neurotransmitters

1. Dopamine 2. Epinephrine 3. Norepinephrine 4. Serotonin 5. Histamine

List 4 amino acids that fall udner small molecules group of neurotransmitters

1. Glycine 2. Glutamate 3. Aspartate 4. GABA

What store small molecule transmitters?

Small clear synaptic vesicles (SSVs)

What store peptides?

Large dense core vesicles (LDCVs)

Which neurotransmitter is present in both types of vesicles?

ATP

Which type of neurotransmitter group is most abundant?

Peptides, far outnumber small molecule transmitters

List and describe the three main features major neurotransmitters share

1. Localization (substance must be present at presynaptic site, usually made by that neuron) 2. Release (must be released in response to presynaptic depolarization, release dependent on extracellular Ca2+) 3. Receptor (on postsynaptic cell, mimicry, given exogenously, get same affect with same amount of substance)

List the 3 approaches for inactivation and which transmitters employ them

1. Enzymatic degradation- ACh, peptides 2. Reuptake- Dopa, norepi, epi, serotonin, GABA, glycine, glutamate 3. Diffusion- Important for all

List the three important catecholamines

Dopamine, epinephrine, norepinephrine

Why use vesicles? (3)

1. Concentration of transmitter- makes it high enough to affect receptor following release into synaptic cleft 2. Separates transmitter pool from metabolic pool and from degradative enzymes- Glu, Gly, GABA, ACh, catchecholamines 3. Essential part of biosynthetic pathway for some transmitters (peptides, norepi and epi)

What is the importance of having vesicles recycle multiple times?

If synaptic vesicles simply fused with presynaptic membrane, the terminal would enlarge and supply of vesicles would be depleted.

Where are synaptic vesicles proteins synthesized?

ER and Golgi, cannot be replenished quickly

The recycling process of synaptic vesicles is fast. ~1 min. List the steps (5)

1. Budding from endosome - exocytosis 2. Docking - exocytosis 3. Priming 4. Fusion of calcium (1msec) 5. Budding with endoome- endocytosis (10-20 sec)

Vesicles nearby, but not at the terminal

Reserve pool

Some reserve pool vesicles are even further away form terminal, often tethered to actin cytoskeleton by this molecule

Synapsin (on surface)

This type of vesicle is siting right next to plasma membrane at active zone.

Docked vesicles

This type of vesicle is not ready to be released quickly

Docked vesicles

An ATP-dependent, multi-step biochemical change has occurred so that this type of vesicle can response to an increase in intracellular Ca2+

Primed vesicle

Form the "readily releasable pool" of vesicles, quickly fusing with the plasma membrane

Primed vesicle

Occurs when calcium concentration is elevated by opening of calcium channels, energetically very unfavorable

Fusion (of membranes)

Studies on mutations affecting membrane trafficking in yeast identified these common set of proteins

SNARE complex

What forms the SNARE complex? [# of helices]

- VAMP/synaptobrevin (vesicular or V-SNAREs) [1] | - Syntaxin [1] and SNAP-25 [2] (target or T-SNAREs on presynaptic membrane)

Before docking, the trans-SNARE complex is not assembled. What proteins organize the trans-SNARE complexes?

Sec/Munc Proteins - act as break to control

This protein acts as a clamp, controlling the "zipping" together of the SNARE complex helices

Complexins (Ca enters and binds synaptotagmin, causes release of complexin, zippering is completed)

The zipping together of the SNARE complex provides enough energy to force the bilayer fusion of what?

The synaptic vesicle and plasma membrane lipid bilayers

True or false: The SNARE complex is Ca2+ sensitive

FALSE. It is not Ca2+ sensitive

Ca2+ binding protein and sensor; triggers Ca2+ dependent SV release

Synaptotagmin

What binds calcium channels directly?

Syntaxin - is at the site of greatest Ca2+ concentration during action potnetial

Ca2+ influx is through what type of channels?

Voltage gated channels (triggers release in less than a msec)

What does Ca2+ binding to synaptotagmin allow?

Final zippering of helices

These proteases disrupt the process of vesicle fusion by cleaving VAMP/synaptobrevin, syntaxin, or SNAP-25

Clostridial toxins/Botulinum toxins

Prevents release of inhibitory transmitters from interneurons by cleaving synaptobrevin, causes over excitation of skeletal muscle, tetanic contractions

Tetanus toxin

Prevents ACh release at neuromuscular junction, causes flaccid paralysis

Botulinum toxin B

After release of neurotransmitter, the SNARE complex needs to be taken apart. What set of proteins disassemble it?

NSF (N-ethylmaleimide sensitive factor) and SNAPs (soluble NSF accessory proteins, alpha, beta, and gamma)

Unraveling the cis-SNARE complex is ATP- independent/dependent

ATP-DEPENDENT. NSF uses 3-6 ATPs to disrupt each SNARE complex.

The average neuron has 10^6-7 vesicles. How many are at any given terminal?

50 vesicles

This synaptic vesicle protein generates electrochemical gradient

Proton pump or V-ATPase

These are examples of vesicular transmitter transporters (3)

VGLUT, VMAT, AChT

Acetylcholine (ACh) is the neurotransmitter at these receptors throughout the autonomic nervous system and brain

1. Nicotinic AChR (ligand-gated ion channels) 2. Skeletal neuromuscular junction 2. Muscarinic AChR (7 transmembrane domain, second-messenger mediated)

The only enzyme unique to ACh synthesis; soluble, cytoplasmic enzyme; not rate limiting

Choline Acetyltransferase (ChAT)

What limits ACh synthesis?

Choline availability

Neurons do not make choline. Choline comes from what two sources?

Hydrolysis of ACh or phosphatidylcholine

What is rate limiting step in ACh synthesis?

Choline uptake at plasma membrane

Cholinergic neurons have a high affinity for choline via what type of uptake system?

Na+ dependent uptake system (CHT1)

Acetyl CoA combines with Choline in the first step of ACh synthesis. What is source of acetyl CoA?

Comes from pyruvate generated by glucose metabolism (used in cytosol by ChAT

This moves acetylcholine form cytosol into synaptic vesicle

Vesicular ACh Transporter (VAChT)

Charge of ACh

positive charge

Transport of ACh is driven by a _____ set up by the ______

Proton gradient, V-ATPase proton pump

V-ATPase proton pump uses energy from ATP to

acidify synaptic vesicles

Uphill/downhill transport of ACh is driven by uphill/downhill flux of protons

Uphill of ACh, downhill of Protons (1-2 H+ leave granule as 1 ACh+ enters)

How many molecules of ACh does each synaptic vessicle store?

6000 molecules

What is also stored in the same vesicles and released with ACh?

ATP

This exteremly fast enzyme is critical for inactivation of ACh

Acetylcholinesterase (AChE)

Sources of ACHE (3)

1. Neurons 2. Target cells (muscle) 3. Glia

Choline generated by AChE is retrieved by

Plasma membrane choline transporter (CHT1) = exclusively cholinergic

CHT1 is stored with VAChT in synaptic vesicles; very little on cell surface until what event?

Exocytosis of vesicles containing ACh

____ gradient established by _____ drives choline retrieval

Na+ gradient; Na+/K+ ATPase

CHT1 resembles what type of transporters?

Na+ dependent glucose transporters, NOT other neurotransmitter transporters

These types of inhibitors are key ingredients in many pesticides (DTT) and nerve gases (e.g. sarin)

Acetylcholinesterase inhibitors (inhibit ACh inactivation)

What is a common result of many snake venoms?

AChR blockade

The major excitatory neurotransmitter

Glutamate

What percentage of neurons in CNS use glutamate as a neurotransmitter?

90%

Glutamate in synaptic vesicles is a small/large percentage of total Glu

Small: 1-20%

Asymmetrical contacts often on dendritic spines

Excitatory synapses

Glutamate is often used to make (4)

proteins, glutathione, GABA, glutamine

Glue does/does not pass the blood-brain barrier

Does not. needs to be made locally

Carbon backbone of brain glutamate comes from ____, which is converted into ______

Blood glucose, converted into alpha-ketoglutarate

To be used asa neurotransmitter, Glu must be concentrated in

Synaptic vesicles

Glutamate concentrations in cytosol vs. synaptic vesicle

Much higher in synaptic vesicle: Cytosolic [Glu] = low mM SV [Glu] = 60-250 mM

This transports Glu into SV

VGLUT (vesicular glutamate transporter). Glutamatergic neurons have VGLUT1 or VGLUT2.

Two important characteristics of VGLUT

1. H+/glutamate antiporter | 2. NOT Na+ dependent

Two factors that drive entry of Glu into SV

High concentration of H+ and positive charge in SC

VGLUTs are activated by _____ and inhibited by ______

Activated by Cl-, inhibited by ketone bodies (links Glu neurotransmission to metabolic state)

Inactivation of Glu is by this process

Reuptake into surrounding glia and pre and post synaptic neurons

Volume of synaptic clef is about 100 x larger/smaller than volume of a single SV

larger

Glu is removed from cleft by this family of transporters

EAAT or EATT 1-5 (excitatory amino aid transmitter transporters)

Certain EATTs are expressed in _____ and others in ____

Glial cells and nerve terminals (EATTs differ in structure from catecholamine transporters)

Concentration of glial EAATs surrounding glutamatergic synapse is very low/high

high- allows for rapid binding of Glu

Uptake of Glu is driven by?

Na+ gradient

Explain how EAATs are Glu symporters

3 Na+ and 1 H+ enter with Glutamate; 1 K+ exits cell; costs 1 ATP for each Glu taken up

Glial cells use this ATP-depdendent cytosolic enzyme to convert Glu into Gln and export it

Glutamine synthetase (NOT found in neurons)

Glutamine release from glial cell (astrocyte) is taken up by neuronal transporter and is driven by

Na+ gradient and membrane potential

This enzyme converts Glutamine that is taken up by pre-synaptic terminal to Glutamate

Glutaminase

This cycle accounts for almost half of the glutamate turnover

Glutamate-glutamine cycle

Disruption of this enzyme in astrocyte rapidly impairs glutamatergic neurotransmission

Glutamine synthetase

Each subunit (monomer) of EAAT functions independently/dependently

independently

Neurons generally use more than one/only one transmitter

MORE THAN ONE.

True or false: the transmitter used by a given neuron can change

True.

EAAT forms

trimers

In EAAT structure, glutamate sits between ______ and interacts with ______

Two hairpin loops, interacts with TMDs 7 and 8

Why may you see convulsant effects in ketogenic diet or fasting?

Ketone bodies (acetoacetate and beta hydroxybutyrate) compete with choride binding site on VGLUT. As result, glutamate can't get transferred into vesicle, and thus less Glu is arriving at postsynaptic cell.

Neurotransmitters 1 Flashcards

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