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Topics in Medical Biosciences > Neuronal Metabolism > Flashcards

Neuronal Metabolism Flashcards

1
Q

What 2 types of intracellular signalling can occur?

A

2nd Messenger signalling (single molecules causing a response such as cAMP and cGMP, Ca2+, NO)
Signalling pathways
(MAP kinase pathways)

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2
Q

What are some physiological roles for intracellular neuronal Ca2+?

A
  • role in synaptic transmission (in mediating neurotransmitter release)
  • role in regulating plasma membrane channels (inhibiting or making neurones excited)
  • role in modulating synaptic plasticity and learning
  • mediate changes in gene expression
  • involved in neuronal development
  • neuronal survival (dependent on Ca/ mitochondria relationship)
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3
Q

What is the involvement of intracellular Ca in neuronal pathology?

A
  • mediator of cell death (necrosis, ischemia (stroke), traumatic brain injury)
  • potential modulator of neurodegenerative processes (Ca2+ hypothesis of Alzhemier’s disease)
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4
Q

What conc of Ca is seen extracellularly compared to in the cytosol?

A

1-2mM outside of the cell
100nM in the cytosol
(100 nM in the nucleus, 0.5mM in the ER, 0.2-20 uM in the Mitochondrion)

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5
Q

What 2 paths are there for Ca entry into the cytosol?

A

Ca entry from extracellular space or intracellular stores (endoplasmic reticulum)

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6
Q

What channel structures are seen in the plasma membrane for the extracellular Ca pathway?

A
  • voltage operated Ca channels
  • receptor operated channels
  • store operated channels
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7
Q

What structures are seen in the ER plasma membrane for the intracellular Ca pathway?

A
  • ryanodine receptors that mediate the process of calcium-induced Ca release (CICR)
  • InsP3 receptor release
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8
Q

Which segments in the alpha 1 subunit is responsible for voltage sensitivity (how does it work) and which is responsible for Ca specificity?

A

Voltage sensitivity is seen in Segment 4 - the depolarisation of the plasma membrane will activate S4 which will generate the opening of the channel and the loop between segment 5 & 6 are for Ca specificity.

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9
Q

What is the structure of the alpha 1 subunit in voltage operated Ca channels?

A

Consists of 4 major transmembrane domains (I-IV) which each consists of 6 transmembrane helices.

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10
Q

What are the differences between the 3 major families of alpha 1 subunits (Cav1 -3)?

A

Difference between the amino acids composition in the alpha 1 subunit and the binding of 3 other auxiliary subunits (alpha2 bound to delta, gamma and beta)

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11
Q

How are Ca Channels distributed in both central and sensory neurons?

A
  • CAV2.1 and CAV2.2 channels are present at pre and post synaptic terminals to modulate response
  • T-type channels are present in dendrites, where they participate in oscillations
  • L-type channels participate in excitation-transcription coupling
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12
Q

How do Receptor/Ligand operated Ca channels work?

A

2 parts of the channel
1 - one part is the receptor that is complimentary to the ligand
2- Second part is the making up of the channel
- As it binds structural modifications occur to activate the channel

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13
Q

What is the most important neurotransmitter in the biological brain?

A

Glutamate

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14
Q

What two types of receptors will glutamate bind to?

A

Ionotropic receptor
- ion related receptor
- as the neurotransmitter binds to the binding site, ions will flow through the channel
Metabotropic receptor
- when glutamate binds to the binding site, this will activate an intracellular signalling protein (most likely G protein coupled) generating Ca release or cAMP release - a 2ndary messenger

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15
Q

What functional classes in ionotropic receptors do not exist in the human brain?

A

NMDA, AMPA and Kainate

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16
Q

What is the structure of a glu ionotropic receptor unit?

A
  • smaller than Ca channel
  • 4 transmembrane domains
  • one cannot go through, generating the M2 loop
  • amino end of protein is extracellular but carboxy is intracellular
  • amino end has glu and modulator binding site
  • carboxy end has the channel forming pore (M2 region)
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17
Q

How many receptor units needed for 1 glutamate receptor?

A

4

- tetradimer

18
Q

What is Ca permeability dictated by in the M2 loop?

A

Dictated by 1 a.a change

  • if R present then no Ca permeability (AMPA/R Receptors)
  • if N present then high permeability (NMDA receptors)
  • if Q present then low Ca permeability (AMPA receptors)
19
Q

What is needed for Ca removal to the extracellular space?

A
  • plasma membrane Ca ATPase (due to huge conc gradient so needs a lot of energy- active)
  • Na-Ca exchanger
    (Na will come in, the energy brings in will be used to push Ca out)
20
Q

What is needed for Ca removal to the intracellular stores?

A
  • SERCA , Sarco(Endo) Plasmic Ca ATPase
21
Q

What are the 3 spatial functional domains of Ca signalling?

A 
Nanodomains:
- high conc, short distances such as activating exocytosis
Intermediate domains:
- medium conc, larger distances
- influence another synapse of dendrite 
Long range domains:
- low conc, larger distances
- Ca enter plasma membrane into the nucleus for gene expression / other activations
22
Q

What are Ca buffers?

A

Proteins that bind to free Ca2+ ions. With a buffer, the concentration will decrease over a certain distance compared to if there was no buffer.

  • when present in cytosol will bind to Ca
  • in cytosol it is parvalbumin and calbindin-D9k
  • in intra-organelle it is calreticulin
23
Q

What are Ca sensors?

A
  • proteins that binds to free Ca and causes a change of conformation that then triggers a range of responses
    (e. g. when Ca binds to Calmodulin, an EF domain is formed)
24
Q

Calcium-calmodulin complexes

A

Mediates Ca sensitive reactions - involved in metabolism, exocytosis and many other roles

25
Q

What is the role of Ca/CaM in activating CamKII?

A

When it binds, alters the conformation of the protein, allowing a domain to phosphorylate. This traps the Ca/CaM domain and keeps the kinase active

26
Q

What types of energy uses would ATP be used for presynaptically?

A

ATP used on 4 types of ATPases:

  • the Na pump
  • Calcium -ATPase in the plasma membrane
  • vacuolar H+ ATPase
  • motor proteins that move mitochondria and vesicles around the cell
27
Q

What types of energy uses would ATP be used for post synaptically?

A

Pumping out of ions mediating synaptic currents

28
Q

What are the 4 pathways glucose can use during its metabolism?

A
  1. Converted into glycogen for storing
  2. Glycolysis then aerobically respire through the TCA cycle in the mitochondria
  3. Glycolysis then anaerobically respire into lactate, catalysed by LDH
  4. G6P can be processed through the pentose phosphate pathway
29
Q

Which glucose transporter is specifically for neurones?

A

Glut3

30
Q

What glucose metabolism pathways are not seen in neurons?

A
  • low affinity for lactate therefore pyruvate will not anaerobically respire
  • glycogen will not be produced as cannot be stored (enzyme is inhibited by a kinase)
  • cannot up-regulate glycolysis when needed due to very little Pfkfb3 activity
31
Q

What are glia cells?

A

“support” cells that bring and keep nervous tissues together

32
Q

What are the different types of glia cells?

A 
Astroglia:
- controlling the neuronal environment 
- contacting blood vessels
Oligodendroglia:
- role in myelination of axons
Microglia:
- "immune" cells of the nervous system
33
Q

How is glucose transported into Glia cells?

A

Glut1

34
Q

What happens to the glucose metabolism inside the Glia?

A
  • can do all 4 pathways
  • low levels of PDH activity so TCA will occur but if higher demand needed, will go towards anaerobic respiration
  • able to up-regulate glycolysis due to high enzyme activity
35
Q

What is the lactate shuttle process?

A

Shuttling lactate from the astroglia into the neuron if up regulation is needed. Then lactate will turn into pyruvate and can undergo TCA.

36
Q

What consequences occur due to Glu uptake by astrocytes?

A
  1. increased [Na} - energetic demand, activate glycolysis and GLUT1 activity
  2. Glu can be used directly in TCA
37
Q

What is the Neurovascular Unit?

A

group of cells closely related to each other - composed by neurones, astrocytes, endothelial cells of blood-brain barrier (BBB), myocytes, pericytes and extracellular matrix components

38
Q

What cells are surrounding the blood vessels in the neurovascular unit?

A

The Glia - astrocytes

39
Q

What mechanism do neurons and astrocytes stimulate for arteriole and capillary dilation in response to synaptic activity?

A

Synaptic activity increases intracellular Ca2+ levels within the post-synaptic neuron. This increase in Ca will trigger the nNOS pathway which synthesises NO (gas) that can diffuse into the blood vessel and can cause vasodilation.
Ca2+ conc increase in presynaptic astrocytes can trigger PGE2 production, (prostaglandin E2) which also has the same affect.

40
Q

What is the two-stage modulation of the NVC response?

A

1st stage is the feed forward mechanism. This is the synaptic activity which is the NO and PGE2 production causing vasodilation.
2nd stage is the feed back mechanism caused by hypoxia in the cell, with the accumulation of the products lactate and CO2

Topics in Medical Biosciences (12 decks)

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