Lecture 5 - Cells of the nervous system 2 Flashcards
What is glutamate?
Glutamate is toxic to nerve cells and can cause nerve cell death
What is neurotransmitter handling?
• Neurotransmitters are molecules released into extracellular space by a neurone that elicit a response in other neurones
• To have full control over the responses produced by a neurotransmitter it is necessary to:
◦ control its release
◦ ensure it does not reach high extracellular concentrations
◦ prevent it diffusing to other neurones where it is not required
What is extracellular space?
- In between nerve cells and supporting cells is extracellular space
- Molecules don’t leave one cell and head to the next, molecules move anywhere, they reach receptors by chance using diffusion.
How has neurotransmitter handling evolved?
- to prevent continuous stimulation of post-synaptic cells
- to alter (shape) the post-synaptic response
- to regulate pre-synaptic release
- to prevent excitotoxicity
- to control the effects on nearby neurones
What types of proteins are involved in neurotransmitter handling?
- Post-synaptic receptors
- Pre-synaptic receptors
- Uptake or degradation mechanisms
- Transporters
- Synthetic enzymes - making the neurotransmitter
What happens at the synapse? (1)
- An action potential arrives in the pre-synaptic terminal
- It causes vesicles to fuse with the pre-synaptic membrane
- The contents of the vesicle (neurotransmitter) are released into the synaptic cleft
What amino acid neurotransmitters are there?
- GABA - an inhibitory molecule
- Glutamate - fats excitatory synapses - when rapid response is needed, travels rapidly across the path way. Used in ear?
- Glycine
What amine neurotransmitters are there?
- Dopamine
- Acetylcholine - an excitatory molecule
- Epinephrine
- Histamine
- Norepinephrine
- Serotonin
What peptide neurotransmitters are there?
- Enkephalins (pain control, endorphins)
- Somatostatin (inhibitory hormone with neural effects on growth, gastrointestinal system)
- Substance P (pain signalling)
How does the synthesis of Glutamate occur? •
• Glutamate – a common amino acid metabolite, not specific to nerve cells, synthesised in many ways. In nerve cell synthesises around the mitochondria.
What is synaptic transmission?
- At the end of the synapse, there are synaptic vesicles
- These synaptic vesicles, contain neurotransmitters
- When an action potential reaches the end of the synapse, these vesicles release their neurotransmitters
- These fuse and carry signals across the synaptic gap
What do transporters do?
- Removal of amino acids and some amines from the synapse
- Glutamate transporters occur in glial and nerve terminal membranes
- Dopamine and serotonin transporters occur in nerve terminal membranes
- The location of these varies
What is the glutamate-glutamine cycle
- Glutamate is removed from the synaptic cleft by the excitatory amino acid transporters(EAATS)
- The EAATS carry glutamate into neurons and glial cells
- Glutamate in glial cells is converted into glutamine by glutamine synthetase
- Glutamine is then transported back into neurons where it is then converted to glutamate
How does a glutamate transporter work?
- After the cell releases glutamate into the synapse
- Glutamate transport pumps the glutamate back into the neuron or neighbouring glial cells
- This protein is the key to regulating glutamate, too much is toxic and the main cause of many neurodegenerative diseases
What are the physiological actions of transporters?
• Transporters can affect the way that the synapse works
What are other forms of neurotransmitter deactivation?
Reuptake by endocytosis
Acetylcholine is deactivated by acetylcholinesterase released by muscles at the neuromuscular junction
Some neurotransmitters are deactivated by enzymes released into the synaptic cleft
What is the first thing occurring during neurotransmitter handling in a post-synaptic cell?
Neurotransmitter activates postsynaptic receptors of which there are two main types:
◦ Ionotropic: results in ion entry to modify receptor potential
◦ Metabotropic: results in a second messenger system within the postsynaptic (and/or sometimes presynaptic) neurone
Neurotransmitter does not enter the post-synaptic cell through the receptors
What is Excitotoxicity?
- Overstimulation of nerve cells
- Leads to nerve cell damage and death
- Can cause brain damage that cant be repaired
- Prominent in research
- Happens within a few minutes of oxygen deprivation
Who first observed Excitotoxicity, and how was it discovered?
Hayashi in 1954
Direct application of glutamate to the CNS caused seizure activity
What happens if there is excess glutamate at the synapse?
• If uptake fails, the post-synaptic neuron can die either rapidly via necrosis (rapid death?), or slowly via apoptosis (controlled death)
What mechanism affects the release of glutamate?
• One proposed mechanism is that ischemia affects the release of glutamate
What mechanism can affect the inability to extract glutamate from the extracellular space?
- Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of important ions
- Glutamate transporters require the maintenance of normal ion gradients in order to remove glutamate from the extracellular space
How can ion gradients reverse the glutamate transporter?
- Glutamate uptake is highly dependent on ion gradient
- Collapse of a sodium gradient will stop glutamate uptake and in some cases will cause a transporter to operate in reverse direction releasing glutamate into the synaptic space
What did Werth discover?
• Werth showed that, upon oxygen and glucose deprivation of less than ten minutes, neuronal swelling, degeneration and death occur in tissue slices.
