Lecture 2: Ion-coupled receptors and the nervous system

Question 1

Describe the key features of phospholipid bi-layers.

Answer 1

They are a very dynamic structure, not just the phospholipids.
They form a barrier around cells, controlling what enters and leaves, which supporting it’s structure somewhat. Only small uncharged particles can permeate through, any hydrophilic molecules will not permeate.
Certain membranes are adapted to facilitate the role of the cell/tissue. (protein, carbohydrate, lipid attachments etc.)

Question 2

Name the types of membrane bound proteins and their functions.

Answer 2

Transporter proteins - allows impermeable molecules into and out of cell.
Enzymes - embedded facing inside or outside of cell.
Cell-surface receptors - used to identify pathogens and foreign molecules, as well as identify endogenous cells and molecules.
Cell-surface identity markers
Cell-to-cell adhesives
Cytoskeleton attached proteins

Question 3

Name the most common ions found in the body.

Answer 3

Potassium (K+)
Sodium (Na+)
Calcium (Ca2+)
Chloride (Cl-)
Iodide (I-)
Iron (Fe3+ or Fe2+)
Magnesium (Mg2+)
Bicarbonate (HCO3-)

Question 4

What are cations and anions?

Answer 4

Cations are positive ions and anions are negative ions.

Question 5

What types of ion channels are there?

Answer 5

Always open
Voltage-gated
Ligand-gated
Mechanically-gated

Question 6

What are two uses for mechanically gated ion channels?

Answer 6

In the ear, vibrations will send electrical signals to the brain.
In the skin, pacinian corpuscles will respond to pressure and vibration.

Question 7

What are the key elements of a neuron?

Answer 7

The cell body (soma)
Axon
Terminal branches + nerve terminals

Other parts include:
Dendrites
Axon hillock (soma to axon)
Axon collaterals
Nodes of Ranvier
Schwann cells
Myelin sheath

Question 8

How is an electrical signal sent along an axon?

Answer 8

An action potential is created at the axon hillock, this will propagate in one direction down the cell. The myelin sheath (lipid rich insulation) speeds up conduction through a process known as saltatory conduction.

Question 9

How does saltatory conduction work?

Answer 9

The myelin sheath (a fatty coating on axon) prevents sections of membrane from sodium influx. Therefore, the positive change inside the cell is close enough to the next opening in the myelin sheath (Node of Ranvier) to induce a signal and not waste time stimulating sections between these two points.

Question 10

Describe an action potential.

Answer 10

The action potential is the way in which signals are sent along a nerve cell.

Question 11

How is resting potential maintained?

Answer 11

By sodium-potassium pumps located on the cell membrane. 2 potassium molecules are moved into the cell for every 3 Na ions moved into cell. This created a relative negative charge inside axon.

Potassium leak channels also line the membrane, these allow K+ to leave the cell, it does this because K+ is being pumped into the cell from the outside and this creates an diffusion gradient of K+ from inside to outside the cell. When K+ leaves the cell via these leak channels the outside becomes more relatively charged.

This resting potential is usually around -70mV.

Question 12

How is an action potential created?

Answer 12

When the contents of the membrane adjacent to a given point reach a positive value known as the threshold, it opens voltage-gated Na+ channels to open and an influx of sodium depolarizes the cell, propagating it to the next Node of Ranvier.

Question 13

What is a refractory period?

Answer 13

Once an action potential has been created, the inside of the cell must be made negative again. When the voltage reaches its most positive value (usually around 50mV), voltage gated potassium channels open and release large amounts of potassium into extracellular space and sodium is pumped out. The transient increased permeability causes an undershoot where the voltage is lower than -70mV.

Another signal cannot be sent in the refractory period.

Question 14

What is a synapse?

Answer 14

Synapses are the interface between upstream nerve cells target cells. Have regions of empty space between the two called the synaptic cleft. As well as

Question 15

How is an electrical signal converted and transmitted across the synapse?

Answer 15

When an action potential reaches the synaptic end bulb, voltage gated Ca2+ channels open and an influx of calcium occurs. Calcium activates an enzyme that separates vesicles from synapsin, which normally holds them in place. Calcium also helps facilitate the binding of vesicles to the membrane for their release.

Question 16

What is the role of neurotransmitters?

Answer 16

Used to transmit signals across synapses. They cross the synapse and bind to complementary receptors on the postsynaptic membrane.

Question 17

What is an ionotropic receptor?

Answer 17

Ligand-gated ion channels that when bound to by neurotransmitter, will cause the influx or efflux of ions, transmitting an electrical signal.

They exert an effect faster than metabotropic receptors.

Question 18

What is a metabotropic receptor?

Answer 18

Neurotransmitter receptors that rely on G proteins to transduce a signal that activates second messengers.

Therefore this is slower than ionotropic receptors.

Question 19

What are ionotropic glutamate receptors?

Question 20

Describe the NMDA receptor.

Question 21

Name a common substance that affects NMDA receptors?

Answer 21

Alcohol, will act as an antagonist to NMDA receptors, decreasing the likelihood of being stimulated. Because NMDA receptors are used in synaptic plasticity and located mainly in the hippocampus and the cerebral cortex, too much alcohol will result in a black out as memory is not able to be recorded, and less excitation in the cerebral cortex results in poor judgement.

Question 22

What is glutamate?

Answer 22

The major excitatory neurotransmitter in the CNS.

Binds to ionotropic receptors to cause influx of calcium and sodium into postsynaptic neuron, generating an action potential.

Question 23

What are the three types of glutamate receptors?

Answer 23

NMDA -
AMPA -
Kainate -

Question 24

What are NMDA receptors?

Answer 24

Ionotropic receptor

Activated when glutamate, glycine, and D-serine bind to it.

Zinc ions, and magnesium play an antagonistic role. Mg is dislodged when depolarization occurs.

Plays important roles in synaptic plasticity and memory, as well as pain transmission, therefore useful as anaesthetic.

Question 25

Discuss an illegal substance that affects NMDA receptors.

Answer 25

Ketamin, it acts as an NMDA antagonist. It binds to the inside of the NMDA like Mg2+ does, therefore requires open NMDA receptors to inhibit them. Because of inhibition, pain is decreased as glutamate cannot transmit signals. Because synaptic plasticity is also impacted, memory loss and loss of consciousness can happen occur with high amounts of ketamine.

Question 26

What is excitotoxicity?

Answer 26

When increases in neurotransmitters occurs, more bind to postsynaptic neuron and causes overload of calcium ions, calcium is a cofactor in many apoptotic enzymes, triggering them and causing cell death.

Question 27

What is multiple sclerosis?

Answer 27

A disease in which the myelin sheath of neurons is attacked by the immune system, creating plaques along its length. This causes axons to become dysfunctional and can damage them. Because activated immune cells release glutamate, this can cause some excitotoxicity also.

Question 28

Why is multiple sclerosis named as such?

Answer 28

From the greek work “skleros” meaning hard, and multiple meaning many. This is because in MS, hard plaques are developed in the myelin sheath along an axon. Similar to atherosclerosis, where plaque builds up inside an artery wall.

Question 29

What treatment plans are there for multiple sclerosis?

Answer 29

Because MS is an autoimmune disease, immunosuppressants are commonly used. The disadvantage to this is that patients will be immunocompromised, resulting in more infections and increase in number of malignancies.

Question 30

What are AMPA receptors?

Answer 30

Ionotropic receptors present in many parts of the brain, and the most commonly found receptor in the nervous system.

Instead of using N-methyl-D-aspartate as agonist, like NMDA receptors, AMPA receptors use AMPA.

Question 31

What is epilepsy?

Answer 31

A disease that is associated with seizures that can vary in size and duration. These seizures are characterised by excessive asynchronous neuronal activity.

Question 32

What is the aetiology of epilepsy?

Answer 32

Aetiology is complex and varied. With an upregulation of mTOR being associated with epilepsy. Tuberous sclerosis complex (TSC) patients have very high chance of having epilepsy. It can also be acquired.

Question 33

What drug can be used to treat epilepsy?

Answer 33

Perampanel

Question 34

How does perampanel work?

Answer 34

It is an AMPA antagonist, this prevents an influx of ions into neurons and preventing inappropriate action potentials.
Recommended as a ‘second line’ treatment. With sodium valproate in males and girls under 10, and iomotrigins for women, as sodium valproate can cause birth defects when taken by pregnant women.

Question 35

What are kainate receptors?

Answer 35

Different from NMDA and AMPA as their selective activation agonist is kainate.

Less understood than the other two, and play only a minor role in signalling at synapses and synaptic plasticity.

Question 36

Is ion transport important for other neurotransmitters?

Answer 36

Yes, for dopamine and serotonin. 2Na+ ions and 1Cl- ion are transported from the synapse to neuron and the favourable energy of this transfer is used to also transport a dopamine or serotonin into the cell.

Question 37

What is dopamine?

Answer 37

Dopamine is an essential catecholamine and neurotransmitter for motor control.
It is essential for motor control and anticipation reward system.

Produced by specialised cells in basal ganglia, substantia nigra.

The more dopamine in a system the less stimulus to trigger movement.

Question 38

What is Parkinson’s disease?

Answer 38

The loss and destruction of dopaminergic cells in the brain.
The substantia nigra is severely depleted in Parkinson’s, therefore less dopamine is produced. This lack of dopamine makes it harder to stimulate direct motor pathways and easier to stimulate indirect motor pathways, resulting in tremors.

Chemical imbalance also results in depression in many Parkinson’s patients.

Question 39

What drugs can be used for the treatment of Parkinson’s?

Answer 39

L-Dopa is a precursor for dopamine, and is converted to dopamine by DOPA decarboxylase in CNS. This means that instead of prescribing dopamine, which would affect all tissues, L-Dopa is converted to dopamine in the brain as a targeted drug.

Question 40

What is the prognosis for Parkinson’s disease?

Answer 40

Will progress even with drugs and eventually become resistant to L-Dopa.

Question 41

What are the effects of cocaine and methamphetamine on the brain?

Answer 41

Cocaine affects the reuptake of dopamine into the presynaptic neuron by inhibiting dopamine transporter (DAT). This increases levels of dopamine in synaptic cleft and keep it there for longer, stimulating reward system.

Methamphetamine is taken into presynaptic neuron by monoamine reuptake proteins (DAT, SERT, etc.) with 2 Na+ and 1 Cl-. Once inside the cell, will replace endogenous neurotransmitter in their vesicles, forcing substances like serotonin and dopamine into the synaptic cleft. Also inhibits the reuptake of monoamine neurotransmitters.

Question 42

What is serotonin?

Answer 42

A monoamine transmitter found in specific regions of the brain such as brain stem and limbic system, responsible for behavioural and emotional responses. Released from the Raphe nuclei in brainstem.

Also in platelets (8% of serotonin)

Also in the gut (90% of all serotonin)

They bind to 5-HT receptors, of which 13 are GPCRs except for 5-HT3, an ion channel transport protein.

Serotonin receptors widely distributed and exert variety of effects. Broadly however, 5HT-1 and 5 inhibitory and decrease cAMP, while 5-HT2, 3, 4, 6, 7 are excitatory and increase cAMP.

Question 43

What disorder is associated with abnormal serotonin levels?

Answer 43

General anxiety disorder (GAD).

Question 44

What are SSRIs

Answer 44

Drugs that inhibit reuptake proteins for serotonin, this keeps serotonin in the synapse for longer. Side effect of taking too much is serotonin syndrome, this can be fatal.

Examples of SSRIs are prozac (fluoxetine), citalopram, and escitalopram.