Lecture 6 - Synaptic transmission II - Neurotransmitters and receptors Flashcards
Small molecules and neuropeptides are released via …
Exocytosis
Small molecules vs peptide transmitters
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
Gaseous neurotransmitters
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
Small-molecule neurotransmitters diffuse…
Small-molecule neurotransmitters diffuse across the synaptic cleft and bind to postsynaptic receptors e.g. glutamate and GABA
Neuropeptides diffuse …
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.
Gaseous transmitters diffuse..
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
Ionotropic receptors
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
G protein coupled receptor
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
Summary of steps in G protein coupled receptor activation
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)
Glutamate receptor
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)
Cys-loop receptors
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
Nitrous oxide
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)
Glutamate
the most common excitatory neurotransmitter in the brain
Glutatmate step summary
Synthesis
Packaging
Exocytosis
Recycling
Glutamate - synthesis
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)
Glutamate - packaging
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
Glutamate - exocytosis
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
Glutamate - recycling
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
Excitatory amino acid transporters (EAATs)
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
Drugs of abuse
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
Classic neurotransmission =
Ionotropic and G protein coupled receptors
Neuropeptide neurotransmission =
G protein coupled receptors
