Neuropharmacology 2 (MODULE 7) Flashcards
What is glutamate?
• Glutamate is the primary excitatory neurotransmitter in the CNS and also has important actions in the PNS, as well.
• It is an amino acid, and it can come from two sources: either
from glucose metabolism in the Kreb’s Cycle or from GABA
metabolism in the glial cells
• It binds several type of receptors… the two most important
for us:
• AMPA and NMDA
What major enzymes are involved in glutamate synthesis?
What do they individually do?
NOTE: glutamate synthesis and cycling between neuron’s and glia. The action of glutamate released into the synaptic cleft is terminated by uptake into neuron’s and surrounding glial cells via specific transporters. Within the nerve terminal, the glutamine released by glial cells and taken up by neuron’s is converted back to glutamate.
*Gluaminase = enzyme that catalyses the conversion of glutamine back to glutamate.
*Glutamine synthase = enzyme that catalyses the conversion of glutamate and ammonia into glutamine. This helps regulate the balance of nitrogen in the body.
*Glutamate dehydrogenase (GDH) = enzyme that plays a key role in the metabolism of glutamate. It catalyzes the reversible oxidative deamination of glutamate to form NH4+. This regulates nitrogen in metabolism.
Where does glutamate synthesis happen?
Presynaptic terminal of the cell
What are EAATs? What do they do?
Glutamate transporters located on the neurons and astrocytes. This regulates the amount of glutamate and prevents excitotoxicity. Responsible for the reuptake of glutamate from the synaptic cleft into nearby cells, such as neurons and glial cells.
Why is glutamate considered to be the most important neurotransmitter in the brain?
It is required for excitation and waking behaviour, learning and memory storage and recall, and management of planning activities. It is also crucial in many reflexes, primarily the Afferent limb of reflex activity. It acts at several types of receptors, notably the AMPA and NMDA sites.
What is the AMPA receptor? What does it do?
The AMPA receptor, when bound by glutamate, acts very quickly to open non-specific channels to both Na+ and K+.
Depolarization (fEPSPs) occur and helps to regulate all types of excitatory activity in the brain and spinal cord.
(*α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor)
What are NMDA receptors and what does they do?
Long term potentiation! Underlies the process of long term memory.
It allows both sodium (Na+) and calcium (Ca2+) to enter the cell and potassium (K+) to leave the cell.
Mg2+ will regulate how quickly Ca2+ can come into the cell.
T or F
There are fewer NMDA receptors than AMPA receptors at excitatory synapses.
T
AMPA sites help keep NMDA sites from allowing too much calcium from entering the cell.
Too much Ca++ coming into the cell causes excitotoxicity: concussion and hypoxia
What is excitotoxixity and how can it occur?
Occurs when too much Ca2+ comes into a cell or there is not enough O2 to run the Ca2+ pumps.
T or F
GABA is inhibitory
T
While calcium transport via NMDA receptors is necessary for long term potentiation (LTP) associated with memory production and neuroplasticity.. too much can lead to?
Too much calcium inside the cell can lead to cellular death via the activation of apoptotic enzymes.
How does antioxidants and glutathione (GSH) help mitigate the effects of ROS driven by Ca2+?
Glutathione is often discussed as an adjunctive treatment for free radicals and ROS created by excess Ca2+
Glutathione is a powerful antioxidant found in the cells of your body. It’s made up of three amino acids: glutamine, cysteine, and glycine. Its primary role is to protect cells from oxidative stress, which can damage the cells and lead to various diseases and aging. Glutathione helps neutralize harmful free radicals and reactive oxygen species (ROS), which are byproducts of normal cellular processes but can be damaging in excess.
Usually cells have highly active calcium pumps that remove excess calcium from cell if levels are too high if there is not adequate ATP do to respiratory hypoxia or other decreases in O2 there will not be an adequate way to get rid of the excess calcium. Therefore if too much glutamate is released do to increased excitation cause by concussion or TBI intracellular levels of calcium can cause cellular death by apoptosis. What can help mitigate these affects and why?
Antioxidants and glutathione can help reduce the affects of ROS that are driven by calcium.
—> Calcium-induced ROS production can cause significant cellular damage, but antioxidants, particularly glutathione, help to neutralize these harmful species, protecting the cell from oxidative damage. Glutathione and other antioxidants work together to reduce ROS levels, maintain cellular function, and prevent long-term damage to cellular structures.
Longer Explanation:
Calcium ions (Ca²⁺) are involved in numerous cellular processes, including signal transduction, muscle contraction, neurotransmitter release, and enzyme activation. However, when calcium levels become dysregulated (e.g., during oxidative stress or injury), excessive calcium can activate pathways that lead to increased ROS production.
Calcium overload can activate enzymes such as phospholipase A2 and NADPH oxidase, both of which contribute to the generation of ROS, particularly in mitochondria and cell membranes.
Antioxidants are molecules that neutralize ROS, preventing them from causing oxidative damage to cells. Antioxidants include enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase, as well as non-enzymatic molecules like vitamin C, vitamin E, and polyphenols.
What are ROS (reactive oxygen species)?
Reactive molecules containing oxygen that can play both beneficial and harmful roles in the body. While they are involved in important processes like cell signalling and immune defuse, excessive ROS can cause oxidative stress, leading to damage to cells and tissues. balancing ROS levels with antioxidants is crucial for maintaining good health.
T or F
Too much glutamate in the cell will overproduce glutathione.
F
Too much glutamate inside the cell will inhibit the cells ability to make glutathione.
What is gamma amino butyric acid (GABA)?
It is known to be the primary inhibitory transmitter in the brain. Synthesis: in neurons, mainly from glutamic acid (glutamate) derived from the Kreb’s cycle
Most GABA is synthesized
from glutamic acid derived from the Kreb’s cycle
The synthetic enzyme is: Glutamic Acid (Glutamate)
Decarboxylase (GAD)
Glutamate will become GABA using what enzyme?
Glutamic acid decarboxylase (GAD)
What are GABA-a receptors? How do they function?
-GABAa receptors are known to be permeable only to chloride.
-It is a complex receptor, however, requiring two ligands to bind to bring about full conductance to chloride.
GABA and an endogenous benzodiazapine must both bind
How does inactivation occur involving GABA?
Inactivation occurs by reuptake (GABA transporters) either into glial cells or back into the presynaptic terminal directly.
In the mitochondria of the glial cells, GABA-Transaminase (GABA- T) transforms GABA back into glutamate, and from there, back to glutamine.
This can be transported back into the “GABA neuron” where glutamine enters the mitochondria to rejoin the Kreb’s cycle.
The brain makes _______ and ________. Both are necessary for what?
GABA and benzodiazepines
Both are necessary for full chloride ion conductance (Cl-) (g)…
Further explained
- when GABA is present, benzodiazepines amplify GABA’s inhibitory effects, making neurons even less likely to fire.
If something inhibits or reduces the function of GABA (e.g., by blocking GABA receptors or reducing GABA production), it can lead to increased neuronal excitability. This hyperexcitability is linked to mood disorders, including anxiety and depression
If there is an issue with benzodiazepine function—for example, in the case of benzodiazepine receptor antagonists or reduced receptor sensitivity—the calming, anxiolytic effects of the drug are diminished. This would result in ineffective treatment for anxiety and potential worsening of symptoms in individuals who rely on benzodiazepines for symptom management.
If Cl- comes into a cell this will cause ________. Why is this significant in the context of GABA?
Hyperpolarization,
GABA is an inhibitor transmitter. GABA + benzodiazepine = the standard amount of Cl- ion necessary for no anxiety.
***diagram on slide 19
T or F
Benzodiazepines (BDZs) are modulators of GABA and NOT agonists
T
What two herbs have been shown to have an action on chloride conductance at the GABA-a receptor site?
Valerian and kava
In the waking times there are higher levels of _______ and during the sleeping time there are higher levels of ______.
Waking = glutamate
Sleeping = GABA
