L1: Synapses and synaptic transmission

What are the four types of NT release?

1) Spontaneous, no action potential involved, calcium-dependent 2)Asynchronous, action potential may be involved, but not in time with the NT release, calcium-dependent

3)Calcium independent 4)Synchronous, action potential and calcium-dependent

What are the events that occur before synchronous NT release

1.Presynaptic Depolarisation

2. Calcium Entry

3. Vesicle Movement & Priming

4. Vesicle Docking

5. Vesicle Fusion

6. Vesicle Recycling

What is the role of voltage-gated calcium channels?

Allow entry of calcium into the pre-synaptic terminal which causes the vesicle to move towards the presynaptic membrane

Which ion generates the action potential ?

Sodium

Which ion returns the electrochemical gradient to its resting state ?

Potassium

Why can the axon hillock be referred to as the spike initiation zone (SIZ) ?

The region is packed with Na/K channels so it can generate powerful action potential

Describe the features of the fastest nerves?

Myelination = jumps from the nodes of ranviers

Larger diameter = less resistance

What causes a broader action potential at the presynaptic terminal?

Calcium entry via voltage-gated calcium channels

What are the two reasons why calcium will enter the cell at high concentrations?

1) Large concentration gradient

2) 2+ charge (the inside of the neurone is negative and calcium has a positive charge)

How can calcium entry be dangerous ?

Uncontrolled calcium entry very rapidly or over a period of time is damaging as many enzymes and ion channels are calcium depending can be toxic and damaging to cells

State the old terminology for the three VOCC subfamilies ?

L-long-lasting) = Cav1

T-transient) = Cav3

N-neither) = Cav2

State the subtypes of Cav1 and their location and role ?

1.1 = Skeletal muscle (contraction)

1.2 = Cardiac muscle

(contraction)

1.3 = Endocrine (release)

1.4 = Retina (NT release)

State the subtypes of Cav2 and their locations and roles?

Subtypes =2.1, 2.2, 2.3

All are located in CNS

Many found pre-synaptically

Role= NT release

State the subtypes of Cav3 and their location and role ?

Subtypes=3.1, 3.2,3.3

All are located in CNS, PNS and Cardiac Muscle

Role = Pacemaker

State the drugs/toxins that selectively block Cav2 ?

w-agatoxin IVA= 2.1

SNX-482 =2.3

State where all of the drug/toxins that block Cav2 come from ?

w-agatoxin IVA = spider (2.1)

w-conotoxin GVIA= snail (2.2)

SNX-482= spider (2.3)

How does the pre-synaptic terminal control NT release ?

- If GPCR is activated => Goby activation => beta & gamma subunit comes off and blocks VOCC => less NT release as less Ca2+ entry (negative feedback)

- Ligand-gated ion channel => more NT release as more Ca2+ entry (positive feedback)

What is the GPCR subtype always coupled to on pre-synaptic terminal?

Go

What is coupled to Go to inhibit the release of ACh

Muscarinic

(M2 & M4)

What is coupled to Go to inhibit the release of Noradrenaline

Alpha 2

What is coupled to Go to inhibit the release of 5-HT

5-HT1

What is coupled to Go to inhibit the release of glutamate ?

mGluR1 & mGluR5

What is coupled to Go to inhibit the release of GABA ?

GABA-B

What is coupled to Go to inhibit the release of dopamine ?

D2

What is coupled to Go to inhibit the release of endorphin/enkephalin?

u (opioids )

What is coupled to Go to inhibit the release of ATP?

P2Y12 ,13 & 14

State the Ca permeant LGIC subtypes which increase NT release for ACh, Glutamate and ATP?

ACh = Alpha 7 nACh

Glutamate = NMDA

ATP = P2x

Define priming ?

The steps before docking/fusion but can also involve some of the docking events

What are the two types of priming ?

1) Positional priming = positioning of NT vesicle in the correct place towards the docking sites

2) Molecular priming = getting the proteins together that do docking & fusion (molecular changes that allow for docking & fusion)

What is the transmembrane protein found in the vesicle membrane ?

Synaptobrevin (1 Snare motif)

What are the three SNARE proteins that are used to dock the vesicle to the presynaptic membrane ?

- Synaptobrevin

- Syntaxin-1

- SNAP-25

State the SNARE proteins that are transmembrane domains needed for vesicular docking ?

Synaptobrevin(found on vesicle membrane) and SNAP-25(anchored to presynaptic membrane)

In normal conditions how many nm away from the plasma membrane does docking occur ?

Between 5 and 40nm

When does synaptobrevin interact with syntaxin-1 ?

When the vesicle gets closer to the membrane ?

What is a SNARE motif ?

particular sequence of amino acids

What is needed for vesicular fusion?

- Calcium

- Positive amino acids

- PIP2

What allows for the vesicle to fuse presynaptic membrane ?

Synaptotagmin-1 bound by 2 calciums and PIP2

Describe vesicular recycling ?

Once the vesicle is emptied the synaptobrevin is placed back into the membrane and vesicular transporter is used for NT to enter vesicle

What is the difference between co-release and segregation release of NT ?

Co-release = vesicles with mixture of NT or two sets of vesicles that carry different NT to same presynaptic terminal

Segregation = one part of the terminal releases one type of NT and the other terminal releases a different NT

What NT co-release in the pineal gland ?

Noradrenaline and 5-HT

What co-release occurs at alpha 1 and P2X receptors?

ATP(P2X) + Noradrenaline (alpha 1) found in the sympathetic vas deferens (in PNS)

What is somatostatin coreleased with in the sympathetic nerves ?

Noradrenaline