neuro: neurotransmitters system I: glutamate Flashcards
what is neurotransmission?
neurotransmission is the fundamental process that drives information transfer between neurones and their targets.
what are neurotransmitters?
neurotransmitters are chemical messengers that transmit signals from a neuron to a target cell across a synapse
what is the criteria for a chemical messenger to be classified as a neurotransmitter?
- the molecule must be synthesised and stored in the pre synaptic neurotransmitter
-the molecule must be released by the pre synaptic axon terminal upon stimulation.
-the molecule must produce a response in the post synaptic cell.
what is glutamate? And briefly explain
glutamate is the major excitatory neurotransmitter in the central nervous system.
it took a long time to realise that glutamate was a neurotransmitter, as it is at the crossroad of multiple metabolic pathways
The excitatory role of glutamate in the brain and spinal cord was discovered in the 1950’s.
how is glutamate synthesised and stored?
- glutamine is converted into glutamate via the enzyme “glutaminase” which is phosphate activated.
- changes the amine group into a carboxylate acid group.
-glutamate is synthesised in the nerve terminals
-once synthesised, glutamate is transferred into vesicles by vesicular glutamate transporters (VGLUT)
-the inside of vesicles are more acidic, have a high concentration of hydrogen ions.
to allow the entry of glutamate, there is a counter transport with hydrogen. hydrogen moves down its concentration gradient, bringing a glutamate inside the vesicles.
how is glutamate synthesised and stored?
- glutamine is converted into glutamate, using the help of glutaminase (which is phosphate activated) which catalyses the reaction.
-an amine group turns into a carboxylate acid group
-glutamate is synthesised in the nerve terminals, and transported into vesicles by vesicular glutamate transporters (VGLUT)
-the inside of synaptic vesicles, is very acidic. The acidity is maintained by ATP driven hydrogen ion pumps. As the hydrogen ions go down their concentration gradient, this allows the glutamate to enter the vesicle, using counter transport.
explain glutamate re-uptake and degradation? And explain what EAAT is
- both neurones and glial cells contain excitatory amino acid transporters which are abbreviated EAAT.
- ‘EAAT’ is a family of five different sodium ion dependant glutamate co transporters.
- these function to transport glutamate from the synaptic cleft back into the neurone/closer cell for degradation.
Degradation:
-before glutamate enters the glial cells for degradation, it is converted into glutamine first by the action of glutamine Synthetase.
-glutamine is transported out the glial cells, using SN1
-glutamine is then transported into the neurones using the SAT2.
what are the two broad families of neurotransmitter receptors?
- ligand gated ion channels (ionotrophic) - membrane spanning domain that forms an ion channel
- g-protein coupled receptor (metabotrophic)- 7 transmembrane domains, extracellukar domain for neurotransmitter binding.
- extracellular domain binding causes the activation of g-Proteins that can dissociate.
Describe the ionotropic (ligand gated) glutamate receptors?
-the ionotropic receptors are named after the agonists that activate them
- AMPA activates ampa
-NMDA activates nmda
-KAINIC ACID activates kainate
NMDA and AMPA make up majority of the excitatory neurotransmission in the brain.
-all the receptors cause an efflux of potassium ions but an influx of sodium ions however NMDA allows influx of sodium AND calcium ions.
describe AMPA receptors?
-they are ionotrophic receptors so contain 4 subunits.
-GLUA1
-GLUA2
-GLUA3
-GLUA4
-these subunits are organised into a hetero-Tetrameric structure.
-most commonly- 2 GLUA2 subunits, 2 GLUA1,3 or 4
-this allows opportunity for 4 binding sites.
-in order for the ion channel opening to occur, two sites must be occupied.
-current increases as more binding sites are occupied.
-the presence of GLUA2 subunit prevents the flow of calcium ions.
-if replaced with GLUA1,3 or 4 subunit, becomes permeable to calcium.
-this is good as intracellular calcium has many excitotoxic effects
describe NMDA receptors
-three subunit types
-GLUN1,2 and 3.
-most common orientation is : 2 GLUN1 subunits , 2 GLUN2/3 subunits.
-the GLUN3 subunits are inhibitory to the NMDA receptor function.
-the NMDA receptors are both ligand and voltage gated.
-the ligands are glutamate and glycine or d-serine
-glutamate binds to GLUN2 subunit, glucine or d serine —> GLUN1 subunit
-all binding sites need to be occupied for ion channel opening.
-NMDA receptors are also voltage gated, so there is a magnesium ion block at the resting membrane potential (so doesn’t let magnesium ions leave at the resting membrane potential). Only once depolarisation occurs, will magnesium ions exit the ion channel and allow the ion channel to be open allowing influx of ions
describe kainate receptors
-5 subunit types :
- GluK 1-5.
-the kainate receptors are tetrameric.
- GLUK1-3 subunits can form homomers or heteromers.
- GLUK4 and 5 only heteromers with gluk1,2,3 subunits.
-kainate are ligand gated only
-number of glutamate binding required for Chanel opening is not very well understood.
-kainate receptors are less distribute in the brain compared to the other glutamate receptors.
describe metabotropic glutamate receptors? (G-protein coupled receptors)
-consists of an extracellukar neurotransmitter binding domain, a 7-transmembrane domain and also a c-terminal domain.
8 types: mGlu1-8.
categorise the mGlu receptors into their groups.
Group 1: mGlu1, mGlu5
Group 2: mGlu2, mGlu3
Group 3: mGlu4, mGlu6, mGlu7, mGlu8.
what orientation do gluatnate metabotrophic receptors subunits form
-the metabotrophic glutamate receptors can produce dimers:
-homomers
- heteromers (eg between mGlu1 and mGlu5)
-heteromers (eg between mGlu2 and other classes of receptors for example the 5-ht2a)
