Excitotoxicity - Karius 3/23

Question 1

Where is aspartate found?

Answer 1

Visual cortex and pyramidal cells

Often with glutamate

Question 2

Is the NMDA receptor ionotropic or Metabotropic?

Answer 2

Ionotropic

Question 3

What does the NMDA receptor allow for when activated?

What else is needed before substance can enter?

Answer 3

Ca2+

Glycine

Question 4

What blocks the channel and prevents the influx of calcium?

When will this blockage end?

Answer 4

Mg2+

When the cell is depolarized

Question 5

What additional binding site is internal to Mg2+ and will block the calcium channel?

Answer 5

PCP binding site

Question 6

Describe the EPSP of the NMDA receptor in terms of onset and duration

Answer 6

Slow onset (Time to remove Mg)

Prolonged duration (Ca slower)

Question 7

What are the types of non-NMDA receptors?

Answer 7

AMPA

Kainate

Question 8

What enters the cell when AMPA receptors are activated?

What other site does it have and what does it do?

Answer 8

Na

Benzodiazepine site (inhibits response to nt)

Question 9

When the kainate receptor is activated what enters the cell?

Answer 9

Na

Little Ca

Question 10

Fx of non-NMDA receptors?

Answer 10

Primary afferents

Premotor (upper mn)

Question 11

Fx of NMDA receptors?

Answer 11

Long-term changes in synaptic strength
Learning
Memory

Question 12

Fx of Metabotropic receptors?

Answer 12

Learning
Memory
Motor systems

Question 13

What gets rid of EAA?

Answer 13

Neurons and glia

Glia

Question 14

How do the neurons get rid of EAA?

Answer 14

Na secondary active transport

High affinity for Glu and Asp only

Question 15

How do the glia get rid of EAA?

Answer 15

Convert to glutamine (inactive form) and release it into the ECF

Question 16

How is NO made in the presence of NMDA receptors?

Answer 16

NMDA receptor activated -> Ca2+ influx -> binds calcineurin -> activates NOS

NOS catalyzes Arg -> NO

Question 17

Neural Fx of NO?

Answer 17

Long-term potentiation and memory

Cardiovascular and respiratory control

Question 18

How can NO be toxic?

Answer 18

Leads to production of free radicals

Kill invading bacteria

Question 19

What happens in the area most directly affected by ischemia?

Answer 19

Oxygen deprivation

Cells unable to meet metabolic needs and depolarization of membrane occurs

Question 20

How does increased Ca influx affect the membrane?

Answer 20

Activation of PLA2 -> release of arachidonate from membrane causes physical damage to it

Question 21

What else does Ca influx do to calcium stores?

Answer 21

Releases Ca from intracellular stores in the ER and mitochondria

Question 22

Release of Ca from ER triggers what?

What does this do?

What does this activate?

Answer 22

Unfolded protein response

Stops making protein

eIF2a-kinase

Question 23

What else does excess Calcium activate?

Answer 23

Mu-calpain (protease)

Question 24

What does mu-calapin do?

Answer 24

Proteolysis of spectrin and eIF4G

Therefore metabolic impairment

Question 25

How does increased calcium influx affect calcineurin?

Answer 25

Activates NOS and INC NO synthesis

Question 26

Disruption of mitochondria and ER function causes what?

Answer 26

INC free cytosolic Ca thus leading to apoptosis

Question 27

What to mitochondria release when dumping their calcium? What do these activate?

Answer 27

Cytochrome C and Caspase 9 Caspase 3 -> apoptosis

Question 28

What happens in a reperfusion injury?

Answer 28

Hypoxic neurons are not normal, oxygen will end up as a free radical

Question 29

When reperfusion occurs, what do kinases do with ATP? What happens?

Answer 29

ATP -> ADP + PO4 Phosphorylation of eIF2alpha kinase leads to a DEC in protein synthesis and activates Caspase 3

Question 30

How can NO add to the cascade?

Answer 30

Causes edema by damaging capillary endothelial cells

Question 31

What are the excitatory amino acids and what do they come from?

Answer 31

Glutamate from alpha-ketoglutarate Aspartate from oxaloacetate