Neurotransmitters & Pharmacology

Question 1

What is meant by synaptic transmission?

Answer 1

Information transfer across the synapse which requires release of neurotransmitters and their interaction w/ postsynaptic receptors

Question 2

Describe Synaptic Transmission referencing to structure of neurones

Answer 2

Information reception through dendrites (contain spines which increase SA to increase receipt of info from other neurones)
Cell body takes part in integration of all the information received
Finally rapid transfer of information in form of AP down the axon causing neurotransmitter release from synaptic terminal

Question 3

3 stages of synaptic transmission

Answer 3

1. Biosynthesis (packing and release of neurotransmitter)
2. Receptor action (on postsynaptic receptors)
3. Inactivation of neurotransmitte

Question 4

Variety of transmitters

Answer 4

Amino acids (glutamate/GABA/glycine)
Amines (noradrenaline/dopamine)
Neuropeptides (opioid peptides)
Vary in abundance CNS tissue concentrations
Mediate rapid or slower effects
Neurones receive multiple transmitter influences which are integrated to produce diverse functional responses

Question 5

What happens during activation of CNS synapse?

Answer 5

AP travels down terminal which activates depolarisation (influx of Na+ and deflux of K+) which causes Ca2+ influx into presynaptic terminal
This activates the exocytotic release of neurotransmitter into the synaptic cleft and diffuses rapidly across and makes contact w/ post synaptic receptors
Excitatory response caused as shown by Na+ influx causing depolarisation for post synaptic cell and so generation of another AP which passes on down to the axon.
Re-uptake of neurotransmitter back in to the pre synaptic membrane into the synaptic vesicles and so can be reused as a neurotransmitter
Or
Enzymatic degradation within the synaptic cleft eg Acetylcholine broken down by acteylcholine esterase
Na+K+ transporter then balances out the ions by releasing Na+ and replacing them with K+

Question 6

What happens when neurotransmitters are released from the presynaptic terminal?

Answer 6

Activation of transmitter release is calcium influx dependent and requires rapid (electromechanical) transduction
Vesicles docked onto presynaptic membrane, primed and undergo fusion so open and allow exocytotic release of transmitter into the synaptic cleft
Empty vesicles are bud off and recycled to form new vesicles

Question 7

How do rapid release rates occur?

Answer 7

Synaptic vesicles are filled with NTs and docked in the synaptic zone
Special proteins on vesicles and presynaptic membrane enable fusion and exocytosis (involved in docking, priming and fusion process)

Question 8

Vesicular proteins

Answer 8

Act as targets for neurotoxins as well being important for the release of NTs

Question 9

Alpha latrotoxin - neurotoxin’s effect

Answer 9

Stimulates transmitter release to depletion
Focuses on cholinergic neurones until acetylene choline levels are depleted at which point muscular paralysis takes place

Question 10

Zn2+ dependent endopeptidases - neurotoxin’s effect

Answer 10

Inhibit transmitter release

Tetanus toxin - causes spasms and paralysis as it inhibits the release of two main transmitters (GABA and glycine)

Question 11

Botulinum - Neurotoxin effects

Answer 11

Causes flaccid paralysis due to complete muscle relaxation
Is a bi-chain molecule where the first chain binds to the nerve terminal (cholinergic) and the second part penetrates the terminal and interacts with vesicular proteins
Botulinum cleaves the peptide bonds inactivating the proteins so no docking and priming of vesicles can take place.
(Used as BOTOX to relax muscles for cosmetic purposes)

Question 12

Transmitter release requirements

Answer 12

Calcium dependent (Ca2+)
Transmitter containing vesicles to be docked on the presynaptic membrane 
Protein complex formation to enable docking and rapid response to Ca2+ entry leading to membrane fusion and exocytosis
ATP (for pumps that refill vesicles with NTs) and vesicle recycling

Question 13

Compare Ion channel-linked receptors vs G-protein-coupled receptors

Answer 13

Ion vs G-protein
Fast response (ms) vs Slow response (s/m)
Mediate all fast excitatory and inhibitory transmissions vs effectors may be enzymes or channels

Question 14

Examples of Ion Channel Linked Receptors

Answer 14

Glutamate
GABA
Acetylcholine at nicotinic receptors

Question 15

Examples of G protein coupled receptors

Answer 15

Acetylcholine at muscarinic receptors
Dopamine
Noradrenaline
Serotonin
Neuropeptides

Question 16

Importance of subunits in ion channel linked receptors

Answer 16

Receptors usually contain 5 different subunits

Multiple subunit combinations create distinct functional properties

Question 17

Compare postsynaptic potentials between excitatory and inhibitory NTRs

Answer 17

Excitatory causes rapid influx of positive ions (Na+ in glutamate receptor) which generates EPSP where membrane potential increases which then returns to normal within 5ms
Inhibitory causes rapid influx of negative ions (Cl- in GABA receptor) which generates IPSP where membrane potential decreases and then returns back to normal mp within 5ms
Balance between two transmitters to keep balance between excitation and inhibition

Question 18

AMPA Receptors

Answer 18

Permeable to Na+ ions
Type of glutamate receptor which mediate majority of fast, excitatory responses to glutamate
Have rapid onset (response), offset and desensitisation

Question 19

NMDA Receptors

Answer 19

Permeable to both Na+ and Ca2+ ions
Type of glutamate receptor which mediates the slow component of excitatory transmission
Serve as coincidence detectors (require another incoming signal before glutamate can combine to receptors) which underlie learning mechanisms
Hippocampus has high density of NMDA receptors

Question 20

Describe the process that takes place in excitatory Glutamate synapse

Answer 20

Glutamate synthesised from glucose via TCA cycle and transamination
Loaded into vesicles
When AP arrives depolarises terminal causing Ca2+ influx which stimulates process of release of NTs which diffuse across synaptic cleft
Glutamate reversible binds to postsynaptic receptors (AMPA and NMDA)
The different ion channels will generate a response to glutamate on the post synaptic cell
Glutamate is inactivated by reuptake back into the presynaptic nerve terminal and can then be reloaded into vesicles and used again
Glial cells also rapidly take up glutamate by excitatory amino acid transporters where it is enzymatically modified by glutamine synthesise to glutamine

Question 21

What happens when balance between inhibitory and excitatory receptors are not maintained?

Answer 21

Too much synaptic glutamate EEG shows increased spiking (showing electrical brain activity) which can lead to seizures (convulsions)
As the glutamate levels go down to normal levels we see glutamine levels increase reflecting on how excess glutamate is metabolised to glutamine in glial cells

Question 22

Epilepsy

Answer 22

Characterised by recurrent seizures due to abnormal neuronal excitability
(Tutorial talks about different drugs used and how they target to decrease epilepsy)

Question 23

Describe the process that takes place in an inhibitory GABA synapse

Answer 23

GABA synthesised by decarboxylation of glutamate by glutamic acid decarboxylase
Loaded into vesicles, AP arrives causing depolarisation and so influx of Ca2+ causes release of GABA into synaptic cleft
GABA reversible binds to post-synaptic receptors which opens a Cl- channel within the receptor allowing chloride influx into the post synaptic cell hyperpolarizing and takes the membrane potential further away from the resting potential making the cells more difficult to excite and reduces AP frequency.
GABA rapid uptake into presynaptic terminal for reuse or uptake by glial cells and modified by GABA-transaminase to succinct semialdehyde (succinate which passes back into TCA cycle)

Question 24

Structure of GABA receptor

Answer 24

Pentameric organisation of GABA A receptor with important binding domains for drugs

Question 25

Drugs that bind to GABA receptor and facilitate GABA transmission are:

Answer 25

Antiepileptic
Anxiolytic
Sedative
Muscle Relaxant