Chapter 8 Part 1: Glutamate

Question 1

What is glutamate?

Answer 1

Glutamate is the ionized form of glutamic acid. It is an excitatory amino acid that causes a powerful excitatory effect on neurons in the brain and spinal cord. All neurons and glial cells contain glutamate because they use it for protein synthesis and cellular metabolism. Neurons that use glutamate as a neurotransmitter have higher concentrations of glutamate than those that do not.

Question 2

How is glutamate synthesized?

Answer 2

The enzyme glutaminase synthesizes glutamine into glutamate.

Question 3

How is glutamate packed into synaptic vesicles?

Answer 3

The transporter proteins called vesicular glutamate transporter (VGLUT) 1, VGLUT2, and VGLUT3 transport glutamate from the cell cytoplasm into the vesicles.

Some neurons store and release glutamate along with other neurotransmitters. Sometimes glutamate and the co-transmitter share synaptic vesicles and sometimes they are segregated such that any given vesicle contains only a single type of transmitter.

Question 4

How is glutamate released from the presynaptic cell?

Answer 4

Glutamate is released from axon terminals through exocytosis. Some cells release glutamate with co-transmitters and some segregate their axon terminals, with any given terminal releasing only glutamate or only the other co-transmitter.

Question 5

How is glutamate released from astrocytes?

Answer 5

When stimulated by an increase in intracellular calcium ion (Ca2+) concentrations.

There are two hypotheses for how astrocytes release glutamate: 1) vesicular glutamate transporters, and 2) channels in the membrane.

Question 6

How is glutamate inactivated?

Answer 6

Glutamate is removed from the extracellular fluid mostly by astrocytes, and sometimes the postsynaptic cell. This is done by glutamate transporters located on the cell membrane called excitatory amino acid transporters (EAATs). There are 5 types called EAAT1 through EAAT5. The main neuronal transporter is EAAT3 and it is found on postsynaptic neurons.

Question 7

What happens to glutamate after it has been taken up by astrocytes?

Answer 7

The enzyme glutamine synthetase catalyzes the reaction to convert glutamate into glutamine. Glutamine is then transported out of the cell and picked up by neurons which synthesize it into glutamate again.

Question 8

How does the brain use glutamate?

Answer 8

Glutamate is used in many excitatory neuronal pathways in the brain. It produces fast excitatory signaling in the nervous system.

Question 9

Which brain structures use glutamate as a neurotransmitter?

Answer 9

1. the pyramidal neurons in the cerebral cortex
2. the parallel fibres of the cerebellar cortex
3. excitatory pathways within the hippocampus

Question 10

Are glutamate receptors ionotropic or metabotropic?

Answer 10

Some receptors are ionotropic and some are metabotropic.

Question 11

What molecules use glutamate receptors?

Answer 11

1. glutamate
2. aspartate
3. other excitatory amino acids

Question 12

Generally, how do ionotropic glutamate receptors work?

Answer 12

Ionotropic glutamate receptors allow for fast signalling by allowing ions to pass through a channel when glutamate binds to the receptor. They are made up of four subunits that form the receptor channel. They depolarize the membrane of the postsynaptic cell and lead to an excitatory response.

Question 13

What are the types of ionotropic glutamate receptors?

Answer 13

1. AMPA
2. kainate
3. NMDA

Question 14

How do AMPA receptors work?

Answer 14

AMPA receptors depolarize the cell by conducting sodium (Na+) ions into it. AMPA receptors are responsible for most fast excitatory responses to glutamate.

Question 15

How do kainate receptors work?

Answer 15

Kainate receptors depolarize the cell by conducting sodium (Na+) ions into it.

Question 16

How do NMDA receptors work?

Answer 16

NMDA receptors conduct Na+ ions and Ca2+ ions to depolarize the cell. Ca2+ acts as a second messenger in the postsynaptic cell. NMDA receptors are special because they require two different neurotransmitters to bind in order to open the channel: glutamate and one of either glycine or D-serine. These are co-agonists.

Question 17

How can the NMDA receptor be blocked?

Answer 17

The NMDA channel can be blocked while at resting potential by magnesium ions because there is an additional binding site for it inside the receptor channel.

Question 18

How can the NMDA receptor be unblocked?

Answer 18

To unblock the channel, the cell must become depolarized which can happen through the activation of other receptors (e.g. AMPA), which will cause the magnesium ions to dissociate from the receptor.

Question 19

What are the types of metabotropic glutamate receptors?

Answer 19

There are eight different types of metabotropic glutamate receptors named mGluR1 through mGluR8 that are divided into three groups.

Group I) mGluR1 and mGluR5

Group II) mGluR2 and mGluR3

Group III) mGluR4, mGluR6, mGluR7, and mGluR8.

Question 20

Describe the Group 1 metabotropic glutamate receptors?

Answer 20

The Group I receptors are located postsynaptically and they mediate excitatory responses by activating the phosphoinositide second-messenger system

Question 21

Describe the Group 2 and Group 3 metabotropic glutamate receptors?

Answer 21

The Group II and Group III receptors are mostly located presynaptically. The Group II and Group III receptors reduce transmitter release by inhibiting cAMP formation.

Question 22

What is long-term potentiation?

Answer 22

Long-term potentiation (LTP) is when synaptic connections are strengthened for a period of at least one hour. It can be divided into two phases: early LTP and longer-lasting LTP. Early LTP only lasts for a few hours. Longer-lasting LTP involves protein synthesis and dendrite spine growth, among other things.

Question 23

What is the role of glutamate in long-term potentiation?

Answer 23

Activation of the NMDA receptor is necessary for the induction of hippocampal long-term potentiation. When the NMDA receptor channel opens, the influx of calcium ions activates the enzyme CaMKII. CaMKII activation is a necessary step in LTP, one consequence of which is insertion of additional AMPA receptors into the membrane of the dendritic spine of the postsynaptic neuron. This increased rate of AMPA receptor insertion in the membrane enhances the sensitivity of the neuron to glutamate.

Question 24

What makes NMDA receptors special?

Answer 24

1. they require a co-agonist in addition to glutamate
2. they have a binding site for Mg2+ ions within the receptor channel
3. they have a channel binding site that recognizes PCP, ketamine, memantine, and MK-801

Question 25

What is excitotoxicity?

Answer 25

When nerve cells are damaged or killed through a process of exposure-induced excitotoxicity because of excessive exposure to glutamate or other excitatory amino acids.