Neurotransmission and neuromodulation

Question 1

What are the two main molecular structures of neurotransmitters?

Answer 1

Amino acid (GABA, Glu, etc.)
Monoamine (DA, 5-HT, NE, …)

Question 2

In terms of quantitative gene expression for synthesis and packaging , what differentiates neurons releasing aa. NTs and neurons releasing monoamine NTs?

Answer 2

Neurons releasing aa. NTs require only a few genes.

Neurons releasing monoamine NTs require more genes.

Question 3

Where is VGLUT-1 mostly expressed? VGLUT-2? VGLUT-3?

Answer 3

VGLUT-1: cortex
VGLUT-2: thalamus
VGLUT-3: only expressed in very specific cell types

Question 4

What is the GABA equivalent of VGLUT and GLT?

Answer 4

VGAT and GAT

Question 5

True of false: GABA is synthesized from Glu.

Answer 5

True

Question 6

Why can L-DOPA be used as a treatment against Parkinson’s disease?

Answer 6

Parkinson’s is caused by a loss of dopamine release in the striatal pathway

L-DOPA is the precursor to dopamine -> more L-DOPA = more dopamine (in eq. conditions)

Question 7

In terms of monoamine synthesis, why could dopamine theoretically be released from 5-HT neurons?

Answer 7

They contain DDC enzymes (dopa decarboxylase), so in the presence of L-DOPA, they could synthesize dopamine + they express VGLUT

Question 8

How is GABA (aa.) synthesized in neurons? How is adrenaline (monoamine) synthesized in neurons? How is serotonin synthesized?

Answer 8

Glu -> GABA

Tyrosine ->L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline

Tryptophan ->5OH-Tryptophan ->Serotonin // only monoamine that is not synthesized from tyrosine

Question 9

What do SVs typically expressed on their bilayer membrane? What are the roles of the respective structures?

Answer 9

-Vesicular NT transporters ->fill SV with NTs
-V-ATPase ->proton pump establishing ion gradient necessary for intake of NTs
-Synaptotagmin -> calcium sensor
-Synaptobrevin (VAMP) ->involved in SV fusion
-Rab 3 or 27 -> docking SV closed to Ca++ channel

Question 10

Why are proton pumps required for the SV to be filled with NTs?

Answer 10

Vesicular transporters rely on H+ gradients (force) to fill SV with NTs

The proton pump fills the SV with H+ (becomes acidic), creating an electrochemical gradient harnessed by the vesicular transporter to import NTs

Question 11

Why are proton pumps costly in energy?

Answer 11

They depend on ATP (they are ATPases)

Question 12

What are two functional characteristics of fast synaptic transmission?

Answer 12

Spatially restricted
Temporally controlled

Question 13

How is the active zone morphologically distinctive from the rest of the plasma membrane?

Answer 13

Electron dense zone

Question 14

What is the difference between the active zone complex and the SNARE complex?

Answer 14

Both complexes are composed of distinct proteins.

The main role of the active zone complex is to dock SV close to Ca++ channels -> yielding spatial specificity

Question 15

Which protein in the active zone complex is most tightly linking the SV to the Ca++ channel? What molecule on the SV interacts with that protein?

Answer 15

RIM
Rab3

Question 16

What happens if KO RIMs (RIM1 and RIM2, only RIM genes in mammals)?

Answer 16

Dramatically impaired exocytosis

Question 17

To which complex does Munc13 belong? What is its role in exocytosis?

Answer 17

Belongs to the active zone complex, but indirectly interacts with SNARE complex.

Munc13 binds to syntaxin via its MUN domain, relieving the inhibition on Munc18, allowing the latter to form a template for the SNARE complex to properly assemble

*Its role is to prime the SNARE complex (vesicle priming) for fusion ->make SVs “readily releasable” *

Question 18

How much time elapses between a presynaptic AP and a postsynaptic AP?

Answer 18

0.13 msec

Question 19

True of false: the exocytosis process in neurotransmission takes longer then the Ca2+-triggered fusion pore opening.

Answer 19

False.

Question 20

What is the core fusion complex composed of?

Answer 20

Synaptobrevin (VAMP), syntaxin, SNAP-25, Munc18

basically SNARE complex + Munc18

Question 21

Under which condition does synaptotagmin interact with the SNARE complex?

Answer 21

If calcium is present

Question 22

What follows KO of Syt1? What follows KO of Syt9?

Answer 22

Abolishment of synchronous and spontaneous release

Abolishment of GABAergic transmission from striatal neurons.

Question 23

How does synaptotagmin trigger exocytosis?

Answer 23

Binds to SNARE complex, creating a pull and twist motion that forces the vesicular membrane and plasma membrane together

Question 24

Do neuromodulator agents generate postsynaptic currents?

Answer 24

Not really, they rather affect the capacity of the receptor cell to respond

Question 25

What are neuropeptides? In what type of neurotransmission are they involved?

Answer 25

Involved in neuromodulation (slow neurotransmission)

Cleaved from precursor proteins (genetic origin), packaged in dense core vesicles,

Question 26

What is the chemical brain hypothesis?

Answer 26

Neuromodulation would have first helped premetazoan to sense environmental cue

Limited diffusion of neuropeptides would have eventually lead to autocrine amplification of signal

Which would have eventually lead to evolution of protosynapse

Question 27

Why would have neuropeptides been an efficient way to communication in early multicellular organisms?

Answer 27

No need for synaptic spatial specificity -> only need the right neuropeptides and the right receptors

Question 28

How are fluorescent NT sensors generated?

Answer 28

Fusion of fluorescent reporter gene to the NT receptor -> binding of NT to receptor generates fluorescence