Flashcards in Introduction to pharmacology and toxicology: Ion channels as molecular targets Deck (30):
Describe what are ion channels and the role they play in the body?
Membrane protein complexes and their function is to facilitate the diffusion of ions across biological membranes (phospholipid bilayer)
Describe what sodium channels are and the structure of them?
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
Describe what potassium channels are?
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.
Describe the structure of potassium channels?
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
How does calcium play a role with potassium?
In order for the pore to activate, the calcium must bind to it to allow the potassium through
Give an example of a potassium channel modulator, explain how it works and its indication?
1. Minoxidil- opens up the potassium
2. Causes hyperpolarisation in smooth muscle cells, muscle relaxation leads to vasodilation
- Treatment of hypertension in combination with a diuretic and beta-adrenoreceptor blocker
Give an example of a sodium channel drug, explain how it works and its indication?
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
Describe what Calcium channels are and the structure of them?
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
What are the three families of calcium channels?
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
What is the role of High voltage activated dihydropyridine- sensitive (L Type) (Cav1.x)?
Affects the cardiovascular section of the body
What is the role of Low voltage activated (T type) (Cav3.x) channels
Affects the pain section of the body which you can use for pain relief
Give an example of a drug that affects the calcium channel, it's effect and its indication?
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.
- supraventricular arrhythmias, angina, hypertension (dose and preparation dependent)
What are TRP Channels?
1. Transient Receptor Potential Channels
2. Channels that sense heat (touching hot plates)
3. Chilli powder activates it's mechanism
What are channelopathies? And give some examples?
1. Diseases or functions caused by ion channels themselves
Epilepsy: Na+, K+ and Ca2+ channels
Diabetes: K+ and Katp channels
Ataxia: K+ and Ca2+ channels
Pain: Na2+ and Ca2+ channels
What channels are involved in epilepsy?
Na+, K+ and Ca2+ channels
What channels are involved in diabetes?
K+ and kATP channels
What channels are involved in Ataxia?
K+ and Ca2+ channels
What channels are involved in pain?
Na2+ and Ca2+ channels
What are ligand gated channels?
1. Also known as Ionotropic receptors
2. Link ligand binding to an ionic flux
3. Heteromeric assemblies of 4 to 5 subunits
Give an example of a ligand gated channel?
Acetylcholine receptor that binds to allow the channel porter open to allow sodium to pass through
Give examples of super family receptor classes, the gated ion it manages and the excitatory action?
1. nAChR - Na+ - excitatory
2. Glutamate (ionotropic) - Na+ - excitatory
3. 5HT3 (serotonin) - Na+ - excitatory
4. Glycine- Cl- - Inhibitory
5. GABAa- Cl- - Inhibitory
What do all structures of the super family receptors share?
1. Subunits to form pentamers (or tetramers)
2. Can have a different combination of subunits
Describe what Acetylcholine receptors are (mainly structure)?
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)
Give an example of a drug that affects the nAChR, it's effect and its indication?
2. Full agonist of nAChR receptor
3. Mimics acetylcholine but not subject to break down by AChE
- Neuromuscular blockade (short duration) for surgery
Give an example of a drug that affects the 5-HT3t, it's effect and its indication?
2. 5-HT3 antagonist
3. Mediates synaptic transmission to the medullary vomiting centre and area postrema
- Nausea and vomiting induced by cytotoxic chemotherapy or radiotherapy (oral or transdermal)
5. Postoperative nausea and vomiting (intravenous)
Give an example of a drug that affects the GABAa, it's effect and its indication?
2. Full agonist of the GABAa receptor
3. Enhances the activity of GABA
- Short term use of anxiety or insomnia, adjunct in acute alcohol withdrawal, febrile convulsions or muscle spasms
What are the three receptor classes of ionotropic glutamate receptors?
3. Kainate receptors
What is the structure of the inotropic glutamate?
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.
How do you open an NMDA receptor and what is the purpose of it?
1. Glutamate to bind to the domain
2. Glycine to act as a co-agonist
3. Purpose: to allow positive ions through