Introduction to pharmacology and toxicology: Ion channels as molecular targets

Question 1

Describe what are ion channels and the role they play in the body?

Answer 1

Membrane protein complexes and their function is to facilitate the diffusion of ions across biological membranes (phospholipid bilayer)

Question 2

Describe what sodium channels are and the structure of them?

Answer 2

1. Voltage gated sodium selective ion channels located next to pore region
2. Exist in the membrane of most excitable cells
3. Sodium channels structure has only one pore-forming alpha sub-unit that’s one six transmembrane domain
4. Can exist with one or two beta subunits

Question 3

Describe what potassium channels are?

Answer 3

1. Regulate cell excitability through different modalities
2. Frequency and shape of action potentials- number of times neurons fire
3. Secretion of hormones- pancreas beta cells regulate secretion
4. Secretion of neurotransmitters
5. Membrane potential- threashold that must be met.

Question 4

Describe the structure of potassium channels?

Answer 4

1. Alpha subunit is made up of 6 transmembrane domain
2. Intracellular N and C (larger) terminus- phophorylation events can change the channel itself
3. S5 and S6 region allow the potassium channel to flow through (pore)
4. S4 has a positive charge- the voltage sensor to sense potential differences in the cell (makes it voltage gated)
5. The pore of the potassium channel is surrounded by 4 alpha subunits

Question 5

How does calcium play a role with potassium?

Answer 5

In order for the pore to activate, the calcium must bind to it to allow the potassium through

Question 6

Give an example of a potassium channel modulator, explain how it works and its indication?

Answer 6

1. Minoxidil- opens up the potassium
2. Causes hyperpolarisation in smooth muscle cells, muscle relaxation leads to vasodilation
3. Indication
   - Treatment of hypertension in combination with a diuretic and beta-adrenoreceptor blocker

Question 7

Give an example of a sodium channel drug, explain how it works and its indication?

Answer 7

1. Lidocaine: blocks voltage gated sodium channels
2. Targets main cardiac sodium channel
3. Indication: ventricular arrhythmias (starts off the heart beat), especially after myocardial infarction
4. For local anaesthesia

Question 8

Describe what Calcium channels are and the structure of them?

Answer 8

1. Voltage gated ion channels present in the membrane of most excitable cells
2. Form hetero-oligomeric complexes- alpha, beta and gamma.
3. The a1 subunit is pore forming and provides the extracellular binding site(s) for practically all agonists and antagonists

Question 9

What are the three families of calcium channels?

Answer 9

1. High voltage activated dihydropyridine- sensitive (L Type) (Cav1.x)
2. High voltage activated dihydropyridine- insensitive (Cav2.x)
3. Low voltage activated (T type) (Cav3.x) channels

Question 10

What is the role of High voltage activated dihydropyridine- sensitive (L Type) (Cav1.x)?

Answer 10

Affects the cardiovascular section of the body

Question 11

What is the role of Low voltage activated (T type) (Cav3.x) channels

Answer 11

Affects the pain section of the body which you can use for pain relief

Question 12

Give an example of a drug that affects the calcium channel, it’s effect and its indication?

Answer 12

1. Verapamil
2. Blocks the voltage gated calcium channels (L type)
3. Blocks calcium influx in myocardial and vascular smooth muscle cells.
4. Leads to a reduction in cardiac and VSM contraction bringing about a dilation in coronary and systemic arteries.
5. Indication
   - supraventricular arrhythmias, angina, hypertension (dose and preparation dependent)

Question 13

What are TRP Channels?

Answer 13

1. Transient Receptor Potential Channels
2. Channels that sense heat (touching hot plates)
3. Chilli powder activates it’s mechanism

Question 14

What are channelopathies? And give some examples?

Answer 14

1. Diseases or functions caused by ion channels themselves
2. Examples:
   Epilepsy: Na+, K+ and Ca2+ channels

Diabetes: K+ and Katp channels

Ataxia: K+ and Ca2+ channels

Pain: Na2+ and Ca2+ channels

Question 15

What channels are involved in epilepsy?

Answer 15

Na+, K+ and Ca2+ channels

Question 16

What channels are involved in diabetes?

Answer 16

K+ and kATP channels

Question 17

What channels are involved in Ataxia?

Answer 17

K+ and Ca2+ channels

Question 18

What channels are involved in pain?

Answer 18

Na2+ and Ca2+ channels

Question 19

What are ligand gated channels?

Answer 19

1. Also known as Ionotropic receptors
2. Link ligand binding to an ionic flux
3. Heteromeric assemblies of 4 to 5 subunits

Question 20

Give an example of a ligand gated channel?

Answer 20

Acetylcholine receptor that binds to allow the channel porter open to allow sodium to pass through

Question 21

Give examples of super family receptor classes, the gated ion it manages and the excitatory action?

Answer 21

1. nAChR - Na+ - excitatory
2. Glutamate (ionotropic) - Na+ - excitatory
3. 5HT3 (serotonin) - Na+ - excitatory
4. Glycine- Cl- - Inhibitory
5. GABAa- Cl- - Inhibitory

Question 22

What do all structures of the super family receptors share?

Answer 22

1. Subunits to form pentamers (or tetramers)

2. Can have a different combination of subunits

Question 23

Describe what Acetylcholine receptors are (mainly structure)?

Answer 23

1. Subunit of 4 transmembrane (TM) domains
2. TM2 from each subunit lines the ion channel pore
3. Sodium flows along the concentration gradient
4. Causes depolarisation of the cell
   - lead to muscle contraction, neurone: increases probability of neurone firing action potential
5. Depending on the subunits assembled, you get different nAChRs for different things (muscle or CNS etc)

Question 24

Give an example of a drug that affects the nAChR, it’s effect and its indication?

Answer 24

1. Succinylcholine
2. Full agonist of nAChR receptor
3. Mimics acetylcholine but not subject to break down by AChE
4. Indication:
   - Neuromuscular blockade (short duration) for surgery

Question 25

Give an example of a drug that affects the 5-HT3t, it’s effect and its indication?

Answer 25

1. Granisteron
2. 5-HT3 antagonist
3. Mediates synaptic transmission to the medullary vomiting centre and area postrema
4. Indication
   - Nausea and vomiting induced by cytotoxic chemotherapy or radiotherapy (oral or transdermal)
5. Postoperative nausea and vomiting (intravenous)

Question 26

Give an example of a drug that affects the GABAa, it’s effect and its indication?

Answer 26

1. Diazepam
2. Full agonist of the GABAa receptor
3. Enhances the activity of GABA
4. Indiction:
   - Short term use of anxiety or insomnia, adjunct in acute alcohol withdrawal, febrile convulsions or muscle spasms

Question 27

What are the three receptor classes of ionotropic glutamate receptors?

Answer 27

1. NMDA
2. AMPA
3. Kainate receptors

Question 28

What is the structure of the inotropic glutamate?

Answer 28

1. Has subunit of the tetrameric complex
2. Made up of an extracellular amino terminal domain
3. An extracellular ligand binding domain of three transmembrane domains composed of three membrane spans
4. A channel lining re-entrant ‘p-loop’ and an intracellular carboxy-terminal domain.

Question 29

How do you open an NMDA receptor and what is the purpose of it?

Answer 29

1. Glutamate to bind to the domain
2. Glycine to act as a co-agonist
3. Purpose: to allow positive ions through

Question 30

Give an example of a drug that affects the NMDA, it’s effect and its indication?

Answer 30

1. Memantine
2. Channel blocker for receptors made up of GluN2A-D subunits
3. Blocks the Ca2+ influx through the receptor associated channel
4. Prevents calcium overload which results in neuronal death
5. Indication: moderate to severe dementia in Alzhemier’s disease