Neurotransmitters

Question 1

What are receptors?

Answer 1

Membrane-spanning proteins comprising a number of subunits

Question 2

What does ligand binding induce in a receptor?

Answer 2

A conformational change

Question 3

What is the hypothesis for the binding of a neurotransmitter?

Answer 3

lock and key hypothesis

Question 4

What does an agonist do?

Answer 4

can bind to, and activate the receptor. Generally has a similar structure to natural ligand

Question 5

What does a partial agonist do?

Answer 5

binds and activates the receptor, but with reduced efficacy compared to agonist.

Question 6

What does an antagonist do?

Answer 6

binds to, but cannot activate receptor; occupies the natural ligand site so it cannot bind

Question 7

What does an allosteric modulator do?

Answer 7

binds the receptor at a different site to alter how receptor responds to ligand (can have positive or negative allosteric modulators)

Question 8

Give features of the nicotinic acetylcholine receptor and how it depolarises

Answer 8

• ligand gated ion channel
• Membrane-spanning protein
• Ionotropic
• Five subunits (2a, B, gamma, epsilon, sigma) arranged to form a pore
• 2Ach binds 2a subunits to open channel
• Na+ (and K+) flow down their electrochemical gradient
• Membrane depolarises (epsp)
• There is a huge diversity of subunits and hence receptors

Question 9

What are the things that something must have in order for it to be identified as a neurotransmitter?

Answer 9

• Must be synthesised by the neuron
• Must be present in synaptic terminal at sufficient concentrations
• Must be released on presynaptic stimulation
• Exogenous application to postsynaptic cell evokes a response
• Mechanism exists for its removal from synaptic cleft

Question 10

What are the three main classes of neurotransmitters?

Answer 10

• Amino acids: e.g. glutamate; glycine’ y-aminobutyric acid (GABA) (synaptic vesicles, 50 nm)
• Amines: e.g. acetylcholine (Ach); dopamine; noradrenaline; serotonin (synaptic vesicles
• Peptides: e.g. enkephalin; substance P; neuropeptide Y (dense-core secretory granules, 100nm)

Question 11

What is co-localisation?

Answer 11

Most synaptic terminals contain multiple neurotransmitters, usually one amino acid, one amine and a few peptides

Question 12

What are the amino acid neurotransmitter functions?

Answer 12

 Glutamate – excitatory

 GABA – inhibitory

Question 13

What are the amine neurotransmitter functions?

Answer 13

 Acetylcholine – NMJ, brain
 Dopamine – movement
 Serotonin (5-HT) – sleep, appetite, arousal

Question 14

What are the peptides neurotransmitter functions?

Answer 14

 Enkephalin – opiate

 Substance P – pain

Question 15

What type of neurotransmitter is the speed of action fastest with and what type is it slowest with?

Answer 15

Speed of action fastest with amino acids and slowest with peptides

Question 16

Where are most neurotransmitters synthesised?

Answer 16

in the terminal, not the cell body

Question 17

What is the general synthesis of neurotransmitters?

Answer 17

1. Enzymes and transporters in terminal
2. Enzymes convert precursors in neurotransmitter in cytosol
3. Transporters load neurotransmitter into vesicles

Question 18

What are three ways in which neurotransmitter is removed from the synaptic cleft?

Answer 18

• Diffusion: e.g. small amines and amino acids (gets excreted
• Reuptake: specific neurotransmitter transporter proteins in terminal and glial membranes. E.g. Choline transporter (reuse transmitter)
• Enzymatic degradation in cleft – followed by uptake of precursors e.g. acetylcholinesterase (AChE) (reuse transmitter)

Question 19

Give features of GPCR effector signalling

Answer 19

• Neurotransmitter activation of a GPCR at the postsynaptic membrane activates a specific G-protein
• GPCRs allow more possibilities in terms of cellular responses and can amplify responses
• G protein activation leads to ion channel gating; ion channel modulation; enzyme activation; activation of secondary paths

Question 20

What do fast and slow excitation in postsynaptic cells do?

Answer 20

• Postsynaptic cell contains both nicotinic and muscarinic receptors
• As an action potential arrives in presynaptic cell acetylcholine is released
• First we see a Fast EPSP due to nicotinic receptor
• Then we see slow EPSP due to muscarinic receptor
• This first EPSP is not enough to take the cell to action potential threshold
• When presynaptic cell fires again in rapid succession the second EPSP will occur over the initial slow EPSP so action potential threshold will be reached

Question 21

Give features of Glutamate

Answer 21

• excitatory
• four different types of receptor:
• AMPA receptor: requires glutamate to open and then allows Na+ influx
• NMDA receptor: requires glutamate PLUS depolarisation to open and then allows Ca2+ and Na+ influx. Needs magnesium to be pushed out to open
   Kainate receptor: ionotropic Na/K channel
   mGluR receptor (3 classes): metabotropic

Question 22

What are the different types of GABA receptor and what are they a key target for?

Answer 22

 GABAA – ionotropic, increase Cl-, fast inhibition
 GABAB metabotropic, increase K+, Decrease Ca2+, inhibition ‘SLOW’
 A key target for therapeutic drugs e.g. anticonvulsants, anti-anxiety – allosteric modulators

Question 23

Are dopamine receptors metabotropic or ionotropic?

Answer 23

metabotropic

Question 24

What are autoreceptors, what do they do and how?

Answer 24

• Autoreceptors are a type of presynaptic receptor
• Autoreceptors are receptors for the neurotransmitter released by the nerve terminal in whose membrane they reside, and when activated these receptors regulate the release of that neurotransmitter
• Usually this takes place in the form of inhibition i.e. negative feedback, but there are some instances when positive feedback is seen
• Though the presynaptic autoreceptor binds the same neurotransmitter as the postsynaptic receptor, it is often a different member of the same receptor family.

Question 25

How do autoreceptors work with control of noradrenaline release from cardiac sympathetic neurones?

Answer 25

• On the presynaptic nerve terminal there are Alpha 2 type adrenoceptors that act as autoreceptors and regulate noradrenaline release
• These alpha 2 receptors are GPCRs that interact with the G protein Gi. The main effect of Gi is to decrease the activity of the enzyme adenylate cyclase, which turns ATP into the intracellular signalling molecule cAMP
• So the effect of activating the alpha 2 receptors is to decrease the concentration of cAMP in the nerve terminal
• As cAMP increases the activity of voltage-gated calcium channels and thus noradrenaline release, the consequence of activating the alpha 2 autoreceptors is to decrease noradrenaline release

Question 26

What does a heteroreceptor respond to?

Answer 26

A different neurotransmitter to the one it has it’s effect on

Question 27

Why is there a huge potential of regulation of presynaptic transmitter release by heteroreceptors?

Answer 27

The extracellular fluid surrounding a neurone in a highly complex ‘soup’ of neurotransmitters and regulatory molecules that may have diffused in from surrounding synapses or even been released by glial cells, so there is a huge potential of regulation of presynaptic transmitter release by heteroreceptors:

Question 28

What is the acetylcholine heteroreceptor?

Answer 28

• The striatum contains a high concentration of dopaminergic synapses.
• The release of dopamine in the striatum is increased by presynaptic nicotinic acetylcholine receptors acting as heteroreceptors
• These nicotinic receptors work in the same way as those at the neuromuscular junction. They are ionotropic receptors gated by acetylcholine
• However, they have a different subunit composition and are more permeable than those found in muscle

Question 29

How does the acetylcholine heteroreceptor regulate dopamine release in the striatum?

Answer 29

• There are two mechanisms by which the presynaptic nicotinic receptors increase dopamine release
• When they are activated the presynaptic nerve terminal becomes more depolarised and so there is a greater influx of calcium through voltage gated channels (calcium stimulates release of neurotransmitter)
• A secondary mechanism is that calcium can enter the nerve terminal through the nicotinic receptor itself
• Nicotinic acetylcholine receptors are one of the most important types of heteroreceptor in the CNS – pretty much every neurotransmitter seems to have its release regulated by these receptors. This includes neurotransmitters involved in the reward and mood pathways and explains why nicotine is such an addictive substance

Question 30

What interacts with nicotinic receptors and changes their function?

Answer 30

A series of peptides produced in the brain

Question 31

What is Lynx1?

Answer 31

a brain peptide that is very important in regulating nicotinic receptors during brain development, especially of the visual system

Question 32

What is Lynx1 a member of?

Answer 32

Lynx1 is a member of a ubiquitous protein superfamily called Ly6: even organisms as simple as C. elegans have genes encoding Ly6 proteins. In the human genome there seems to be 27 genes coding for Ly6 proteins but the function of most of them is unknown

Question 33

What is Lynx1 similar to?

Answer 33

• The structure of Lynx1 is very similar to that of the a-neurotoxins (snake toxins that target the muscle nicotinic acetylcholine receptors), the a-neurotoxins are also members of the Ly6 protein family
• Lynx 1 is a soluble protein regulator of neuronal nicotinic receptors. It is very important in brain development. In hollow fanged (elapid) snakes, proteins related to Lynx 1 have evolved to become toxins. They target muscle nicotinic acetylcholine receptors. Examples include a-cobra toxin and a-bungarotoxin and Alpha conotoxin M1.