Neurology: Physiology - Neurotransmitters

Question 1

What are the two types of receptor?

Answer 1

1. Ionotropic (ligand-gated)
2. Metabotropic (GPCR)

Question 2

Four type of small molecule neurotransmitters

Answer 2

4 As:
1. Amino acids (glutamate, GABA, glycine)
2. ATP
3. ACh
4. MonoAmines (NA, adrenaline, dopamine, 5HT)

Question 3

What are heteroceptors?

Answer 3

Receptors which respond to chemicals other than the release transmitter (e.g. NA binding to heteroceptor on cholinergic nerve to inhibit ACh release)

Question 4

Describe homologous vs heterologous desensitisation

Answer 4

In respond to prolonged exposure to ligand, receptors undergo desensitisation in one of two ways:
- Homologous: only to ligand specific to receptor
- Heterologous: unresponsive to other ligands as well

Question 5

How does reuptake of neurotransmitters occur?

Answer 5

Via high-affinity, Na+-dependent membrane transporters

Question 6

Why is glutamate reuptake especially important?

Answer 6

Is an excitotoxin which can kill cells by overstimulating them (may play a role in stroke and neurodegenerative disease)

Question 7

What are the two types of reuptake transporters?

Answer 7

One only for glutamate, and co-transports Na+ in and K+ out
Other co-transports Na+ and Cl-

Question 8

What is the main excitatory neurotransmitter in the brain and spinal cord? What % of excitatory CNS neurotransmission does it account for?

Answer 8

Glutamate (~75% of CNS)

Question 9

Describe the synthesis and reuptake of glutamate

Answer 9

Synthesised from a-ketoglutarate in Krebs cycle, via action of GABA transaminase
Glutamate released from nerve terminal and transported into glia via glutamate reuptake transporter, then converted to glutamine by glutamine synthetase -> diffuses back into nerve terminal and hydrolysed back to glutamate by glutaminase (can also be directly taken up back into nerve terminal from synapse via membrane transporters)

Question 10

What are the three subtypes of ionotropic glutamate receptors and how does each function?

Answer 10

All ionotropic
1. AMPA: Na+ influx, K+ efflux
2. Kainate: Na+ influx, K+ efflux
3. NMDA: Ca2+ and Na+ influx

Question 11

Where are AMPA receptors found?

Answer 11

In glia and neurons

Question 12

Where are kainate receptors found?

Answer 12

In glia and neurons
Presynaptically on GABA-secreting neurons, postsynaptically various

Question 13

What mechanism is the major basis for glutamate excitotoxicity?

Answer 13

Ca2+ influx (via NMDA receptor activation)

Question 14

How are NMDA receptors activated?

Answer 14

By glutamate binding, but also requires glycine binding to facilitate
Receptor activation is also blocked by extracellular Mg2+ at normal membrane potential and so there must also be partial depolarisation by adjacent AMPA/kainate receptors

Question 15

How does the speed of EPSPs generated by AMPA and kainate receptors vs NMDA receptors compare?

Answer 15

AMPA/kainate: fast EPSPs
NMDA: slow EPSPs

Question 16

Where are NMDA receptors found and what is their role in the CNS?

Answer 16

In neurons only (not glia)
May play a role in memory/learning

Question 17

How many types of glutamate receptors are there?

Answer 17

3 ionotropic (AMPA, kainate, NMDA) and 8 metabotropic

Question 18

What are the mechanisms by which the metabotropic glutamate receptors work?

Answer 18

Either by increasing IP3/DAG or decreasing cAMP

Question 19

What is the main inhibitory neurotransmitter in the brain and spinal cord?

Answer 19

Brain: GABA
Spinal cord: glycine

Question 20

Describe the synthesis, reuptake and metabolism of GABA

Answer 20

Synthesised from glutamate by glutamate decarboxylase (GAD)
Metabolised to succinate in the Krebs cycle by GABA-T
Reuptake via GABA transporter (with transport into vesicles via VGAT)

Question 21

Describe the location and mechanism of action of the three GABA receptor subtypes

Answer 21

GABA(A): widely distributed in CNS, ionotropic and allows Cl- influx to produce fast IPSP
GABA(B): widely distributed in CNS, metabotropic with Gi inhibiting adenylyl cyclase resulting in increased K+ efflux, and G0 inhibiting Ca2+ influx
GABA(C): exclusively in retina, ionotropic and allows Cl- influx to produce fast IPSP

Question 22

What is the purpose of the chronic low-level stimulation of GABA(A) receptors by GABA in the CNS interstitial fluid?

Answer 22

Decreases “noise” (incidental discharge)

Question 23

On what receptor and to what subunit do benzodiazepines bind to exert their effects?

Answer 23

a subunit on GABA(A) receptors

Question 24

To what receptor do barbiturates bind to exert their effects?

Answer 24

Bind GABA(A) as agonist
Bind and inhibit AMPA

Question 25

Is glycine an excitatory or inhibitory neurotransmitter?

Answer 25

Does both

Question 26

How does glycine exert its excitatory and inhibitory effects?

Answer 26

Excitatory: permissive action on glutamate transmission via NMDA binding Inhibitory: direct inhibition (primarily in brain and spinal cord) via pentameric Cl- channel

Question 27

What neurotransmitter is antagonised by strychnine? How does this present clinically?

Answer 27

Glycine Causes convulsions, muscle hyperactivity

Question 28

Five sites that acetylcholine functions as a neurotransmitter

Answer 28

1. Neuromuscular junctions 2. Autonomic ganglia 3. Postganglionic parasympathetic nerve-target organ junctions 4. Some postganglionic sympathetic nerve-target organ junctions 5. Basal forebrain and pontomesencephalic cholinergic complexes in the brain

Question 29

For which nerves in the CNS does acetylcholine act as a neurotransmitter?

Answer 29

All nerves EXITING the CNS: cranial nerves, motor neurons, preganglionic nerves

Question 30

Describe the synthesis and metabolism of acetylcholine

Answer 30

Synthesised from choline and acetyl CoA by choline acetyltransferase (ChAT) -> forms ACh (CoA taken up by mitochondria for reuse) Hydrolysed to choline and acetate via acetylcholinesterase in synaptic cleft (choline reabsorbed)

Question 31

What two types of acetylcholine receptors are there? Where is each found?

Answer 31

1. Muscarinic: found within brain, and in smooth muscle and glands 2. Nicotinic: found in skeletal muscle at NMJ [N(M)], and in CNS and autonomic ganglia [N(N)]

Question 32

Where are many of the CNS ACh receptors located and what is their function?

Answer 32

Presynaptically on glutamate-secreting neurons to facilitate release

Question 33

Describe the five subtypes of muscarinic receptor: their distribution and mechanism of action

Answer 33

M1: found in CNS and autonomic ganglia, increases IP3/DAG to increase Ca2+ M2: found in heart, decreases cAMP to increase K+ M3: found in smooth muscle and glands, increases IP3/DAG to increase Ca2+ M4: found in CNS, decreases cAMP to increase K+ M5: found in CNS, increases IP3/DAG to increase Ca2+ (Can't EVEN cAMP, ODD and DAGgy)

Question 34

Name one agonist and one antagonist of muscarinic receptors

Answer 34

Agonist: muscarine (from toadstools) Antagonist: atropine

Question 35

What is the structure and mechanism of action of nicotinic receptors?

Answer 35

Pentameric ligand-gated ion channels that increase Na+ influx to produce depolarisation

Question 36

Where is serotonin found in its highest concentrations?

Answer 36

Platelets GIT (enterochromaffin cells and myenteric plexus) Midline raphe nuelci in brain (lower concentrations)

Question 37

Describe the synthesis, release and metabolism of 5HT

Answer 37

Synthesised from the essential AA tryptophan - Tryptophan -> 5-hydroxytryptophan via tryptophan hydroxylase (rate-limiting step) - 5-hydroxytryptophan -> 5HT via L-amino acid decarboxylase - Transported into vesicles for release by VMAT Reuptake of released 5HT occurs via SERT membrane transported - Then either repackaged in vesicles or metabolised to 5-HIAA via MAO

Question 38

What is the clinical significance of 5-HIAA?

Answer 38

Urinary metabolite which can be used to measure 5HT metabolism

Question 39

How many classes of 5HT receptor are there and what is their structure and function?

Answer 39

All except 5HT3 are GPCRs 5HT3 is an ionotropic receptor which increases Na+ influx

Question 40

What is the clinical relevance of 5HT3?

Answer 40

Role in vomiting (present in GIT and in area postreme of brain)

Question 41

What is the role of 5HT2A receptors?

Answer 41

Cause platelet aggregation and smooth muscle contraction