Lecture 6 - Synaptic transmission II - Neurotransmitters and receptors

Question 1

Small molecules and neuropeptides are released via …

Answer 1

Exocytosis

Question 2

Small molecules vs peptide transmitters

Answer 2

Small molecule transmitters cause big transient and rapid changes in membrane potential whereas the peptide transmitters tend to make small and much longer lasting changes to membrane potential - what many think that peptide transmitters do is that they just nudge membrane potential up or down a little bit to make it easier or more difficult for the glutamate EPSPs to reach threshold so modulating excitability rather than triggering the action potentials themselves - this is inferred and it is not scientific fact

Question 3

Gaseous neurotransmitters

Answer 3

Gaseous transmitters diffuse anywhere and into the synaptic cleft (can have an effect on neighbouring cells)

There is no receptor for gaseous neurotransmitters, they interact with enzymes in biosynthetic pathways and modulate their activity

Diffuse freely because they are lipophilic

Question 4

Small-molecule neurotransmitters diffuse…

Answer 4

Small-molecule neurotransmitters diffuse across the synaptic cleft and bind to postsynaptic receptors e.g. glutamate and GABA

Question 5

Neuropeptides diffuse …

Answer 5

Neuropeptides diffuse in the extracellular space and bind to synaptic and extra synaptic G-protein complex receptors
Oxytocin, vasopressin, TSH, LH, GH, insulin, and Glucagon are neuropeptides.

Question 6

Gaseous transmitters diffuse..

Answer 6

Gaseous transmitters diffuse directly out of the cell of origin and directly into other cells. They can act inside the cell of origin or in cells distant from that point of release e.g. nitrous oxide

Question 7

Ionotropic receptors

Answer 7

Receptors that are themselves an ion channels 
When ligand (neurotransmitter) is not bound, the channel is closed 

Steps
Neurotransmitter binds
Binding of the neurotransmitter causes channel to open
Ions flow across membrane (chan

Question 8

G protein coupled receptor

Answer 8

Start of a second messenger system (metabotropic)
For acetylcholine, biogenic amines, neuropeptides, purines

Steps
Neurotransmitter binds - Binds to cell surface receptor because the neurotransmitter is not lipophilic and therefore cannot cross the membrane so it has to do something on the outside that then gets related as a message to the inside
G protein is activated
G protein subunits or intracellular messenfers modulate ion channels
Ion channel opens
Ions flow across membrane

Question 9

Summary of steps in G protein coupled receptor activation

Answer 9

the alpha, beta, gamma g protein complex is attached to the receptor and once it is activated by the transmitter, the G protein dissociates which then goes and does something to another protein known as the effector protein and this is the protein that causes the effect/final action of the activation of that receptor. Here it is the activation of an ion channel which allows ions to flow across the membrane which causes change in the voltage across the membrane so it causes depolarisation (more positive, closer to threshold, excitatory) or hyperpolarisation (more negative, away from threshold, inhibitory)

Question 10

Glutamate receptor

Answer 10

Comprised of an alpha, beta, gamma and delta subunit
4 subunits and 3 transmembrane domains
Composition of subunits determines receptor subtypes
Includes NMDA, AMPA and kainite receptor subtypes (depends on subunit composition)
All have the same ion channel therefore all are excitatory - Na+, Ca2+ (both are excitatory ions and cause depolarisation)

Question 11

Cys-loop receptors

Answer 11

e.g. GABA, glycine, serotonin (5-HT3 receptor), acetylcholine (nicotinic receptor), purines (P2X receptors)
Five subunits, four transmembrane domains
Some inhibitory and some excitatory - depends on selectivity
Cl- and K+ cause hyper polarisation
Na+ and Ca2+ cause depolarisation

Question 12

Nitrous oxide

Answer 12

No receptor

Arginine is converted to citruline by nitrous oxide synthase and the nitrous oxide produced can diffuse across from the presynaptic cell to the post synaptic cells and acts on soluble guanylyl cyclase which is an enzyme in the post synaptic cell and it changes the activity of this enzyme and this uses energy to change GTP into cGMP (second messenger system that changes the activity within the cell). The nitrous oxide is completely lipophilic so it can go anywhere to neighbouring cells and affect other cells with this enzyme if it is close enough

Similar for carbon monoxide, produce by heme oxygenate (replaces nitric oxide synthase in the diagram)



Question 13

Glutamate

Answer 13

the most common excitatory neurotransmitter in the brain

Question 14

Glutatmate step summary

Answer 14

Synthesis
Packaging
Exocytosis
Recycling

Question 15

Glutamate - synthesis

Answer 15

Glutamate has to be synthesised and it is synthesised from glutamine to glutamate which is converted by the enzyme glutaminase (this enzyme is taking something off of glutamine to create glutamate)

Question 16

Glutamate - packaging

Answer 16

Glutamate is packaged into vesicles and this packaging is energy dependent so it requires the activity of an ATPase and this powers the vGLUT (vesicular amino acid transporter) to pump the glutamate into the vesicles and pumping it up its concentration gradient therefore requires an energy source which in this case is ATP

Question 17

Glutamate - exocytosis

Answer 17

Exocytosis of the vesicle, action potential arrives and voltage gated calcium channels open, calcium influx, triggers vesicle fusion and there is release into the synaptic cleft and there is diffusion across the synaptic cleft to activate glutamate receptors on the post synaptic cell

Question 18

Glutamate - recycling

Answer 18

Recycling of the neurotransmitter, it involves the glial cells which in this case is an astrocyte. It expresses another couple transporters (EAAT1 and 2) which mops up any of the extra glutamate that vets released, and it is converted back to glutamine by glutamine synthase and pumped out of the astrocyte and back into the axon terminal by EAAT5

Shows that glia are not just the glue that holds the brain together but that they are active players in the communication between brain cells

Question 19

Excitatory amino acid transporters (EAATs)

Answer 19

These transporters are moving the glutamate (sometimes the glutamine) against the concentration gradient which requires energy and in this case the energy is derived from being a co-transporter with other things that are going down their electrochemical gradient like sodium

Question 20

Drugs of abuse

Answer 20

Drugs cause physical changes in the brain and it changes your perception by interacting with networks in the brain

Example = Methamphetamine (P)
Increases levels of noradrenaline, dopamine, serotonin
Stimulates fight, flight or fright response - Panzerschokolade
Stimulates reward centres
Highly addictive
Highly neurotoxic

Long term use leads to more difficulty reversing the effects

Question 21

Classic neurotransmission =

Answer 21

Ionotropic and G protein coupled receptors

Question 22

Neuropeptide neurotransmission =

Answer 22

G protein coupled receptors