Chemical signalling: Glutamate and GABA Flashcards
What happens during synaptic transmission?
AP reaches the synaptic terminal. Neurotransmitters are released and diffuse across the synaptic cleft. Receptors recognise the neurotransmitters and initiate a response. Results in:
- Direct excitatory or inhibitory neurotransmission - i.e. the next cell fires an AP or is inhibited.
- Neuromodulation - alter the presynaptic cell’s ability to release more transmitter or the postsynaptic cells ability to respond.
What are classical neurotransmitters?
Classical = amino acids (e.g. GABA and glutamate. Responsible for fast transmission. Switch on and off using glutamate, making the next postsynaptic neuron fire. Glutamate is excitatory: causes the next neuron to fire a nerve impulse. GABA applies breaks on a neuron, making it difficult for the neuron to fire an AP). Monoamines (e.g. dopamine and serotonin. Involved in controlling your mood). Acetylcholine.
This are all synthesised locally in the presynaptic terminal. Stored in synaptic vesicles. Released in response to local increased in Ca2+.
What are neuropeptides?
e.g. endorphin. Synthesised in the cell soma and transported to the terminal. Stored in secretary granules. Released in response to global increase in Ca2+. Global increase in Ca2 leads to a strong depolarisation. A more intense stimulation is necessary to release neuropeptides, and hence a more global increase in calcium.
What is the criteria for a neurotransmitter?
- Chemical is synthesised presynaptically.
- Electrical stimulation leads to the release of the chemical.
- Chemical produces physiological effect.
- Terminate activity - activity has to be terminated somehow, e.g. degraded, depolarised.
What is involved in glutamate synthesis, storage, release, and reuptake?
- Synthesised in nerve terminals from glucose or glutamine.
- Loaded and stored in vesicles by vesicular glutamate transporters.
- Released by exocytosis (Ca2+ dependent mechanism)
- Acts at Glutamate receptors on postsynaptic membrane
- Reuptake by excitatory amino acid transporters (EAATs) in the plasma membrane of presynaptic cell and surrounding glia. Support cells are glia.
How is the release of amino acid transmitter regulated?
o Too much glutamate/too little GABA hyper excitability – epilepsy (cased by stroke, infection, trauma). If goes above a threshold, get negative symptoms of epilepsy.
o Over excitation is deadly, as neurons will die. If lose it, cannot regain these neurons back.
o Can also get Cerebral ischemia (insufficient blood flow due to plaque, tumor). Symptoms: weakness, visual impairments. The metabolic events that retain the electrochemical gradients are abolished. Reversal of the Na+ : K+ gradient. Transporters release glutamate from cells by reverse operation. Excitotoxic cell death due to high glutamate.
How to receptors vary in their pharmacology?
What transmitter binds to the receptor and how drugs interact. Agonist = a drug (or endogenous ligand/neurotransmitter) that can combine with a receptor on a cell to produce a cellular reaction. Antagonist = a drug that reduces or completely blocks the activity of the agonist or endogenous ligand, no cellular effect after interacting with receptor. Antagonist alone has no effect, but when combined with agonist, can reduce/block activity, of either a drug or something naturally occurring in your brain.
How do receptors vary in their kinetics?
Rate of transmitter binding and channel gating determine the duration of effects.
How do receptors vary in their selectivity?
What ions are fluxed (Na+, Cl-, K+ and/or Ca2+). Allows certain things in, but blocking others – what this is depends on the type of receptor.
How do receptors vary in their conductance?
The rate of flux. How fast something is flowing inside the receptor.
What is an excitatory transmission?
GABA ionotropic receptors flux Cl-, which causes an IPSP (Inhibitory Post Synaptic Potential) hyperpolarizing the postsynaptic neuron.
What is an inhibitory transmission?
o (Acetylcholine, serotonin and ATP also activate ionotropic receptors)
o Integration of all the changes in membrane potential will decide whether a postsynaptic neuron will fire an action potential or not.
o All bind glutamate, allow positive to come in and depolarise the membrane.
What is glutamate receptor diversity?
Based on their pharmacology, three type of ionotropic receptor have been described that respond to glutamate – NMDA, AMPA and Kainate. They are named based on the agonists selective for them. Key receptors involved in excitatory transmission are NMDA and AMPA.
What is an AMPA receptor?
Ionotropic receptor. Binding of glutamate leads to the opening of a Na+ channel (slight K+ permeability) and hence depolarisation. Sodium comes in, and the membrane is depolarised.
What is an NMDA receptor?
Allow glutamate to bind, but need a co-agonist (glycine) – need both to bind. NMDA receptor is blocked at rest – if there is a blockage which is there at rest, nothing flows in (AMPA doesn’t have this issue). Also have a non-competitive antagonist site. Because of the clogging of the receptor, nothing happens when glutamate is bound at rest. When the neuron gets more excited, this is where the blockage is removed and glutamate binds and calcium enters. Both receptors have different functions due to differences in how they act.
