Ion channels as drug targets Flashcards
Why is an ion channel necessary?
Ionsare charged molecules and unable to cross the plasma memb due to the arrangment of the hydrophilic heads and hydrophobic tails of the lipid bilayer
Give 2 distinctive features of ion channels?
- The rate of ion transport through the channel is very high
- Ions pass through channels down their electrochemical gradient
What are the 2 ion channel selectivity?
Cation channels: Selective for positive molecules/ions, Na+, K+, Ca2+
Anion channels: Selective for negative molecules/ions, Cl-
What is the selectivity filter?
The narrowest region of an ion channel pore.
Ions go in single file through the ion channel
What are the 3 types of ion channel gating?
Voltage-gated channels (VOCs)
Ligand-gated channels (ligand causes conformational change->channel opens)
Receptor-operated channels
What are the 2 ways of activation of excitable cells (depolarisation)?
- An increase in membrane permeability to Na+
- An increase in intracellular due to:
- Release from intracellular Ca2+ stores (ER/SR
- Increased membrane permeability to Ca2+
How is a ion gradient maintained?
Ion pumps i.e. ATPase such as the Na+/K+ pump
The relative impermeability of the cell membrane
Give an example of Classification by Molecular Structure (Number of Gates) and its importance?
Example: Voltage-gated sodium channels (Nav)
Importance: These channels have a single gate that opens and closes based on voltage changes. Understanding their structure helps in drug development for conditions like epilepsy and cardiac arrhythmias.
Give an example of Classification by the Nature of Gating and its importance?
Example: Ligand-gated ion channels (e.g., Nicotinic Acetylcholine Receptor)
Importance: These channels open in response to specific molecules (ligands), playing a crucial role in neurotransmission and synaptic signaling.
Give an example of Classification by Type of Ions Passing Through the Gates and its importance?
Example: Potassium channels (e.g., K+ leak channels)
Importance: Different ion channels allow the passage of specific ions, affecting cellular functions like maintaining resting membrane potential and action potentials.
Give an example of Classification by Cellular Localisation and why is it important?
Example: Voltage-gated calcium channels in presynaptic neurons
Importance: Their location (e.g., in neurons or cardiac cells) determines their function, influencing neurotransmitter release and muscle contraction.
Give an example of other classification of Duration of Response to Stimuli and why is it important?
Example: Transient Receptor Potential (TRP) Channels (e.g., TRPV1)
Importance: Some ion channels respond quickly to stimuli (e.g., action potentials), while others maintain prolonged responses (e.g., pain perception in TRPV1 channels). This affects how signals are processed in the nervous system.
What are the 3 states that a voltage gated ion channel exists in?
Resting: channel closed, this prevails at the normal resting potential
Activated: open state favoured by a brief depolarisation
Inactivated: Blocked state resulting from a trap door like occlusion of the channel by an intracellular floppy part of the channel protein
What are the antagonists for nicotinic receptors?
Non-depolarising neuromuscular blockers, depolarising neuromuscular blockers
What is the difference between Metabotropic and ionotropic?
Ionotropic no 2nd messenger required
Metabotrophic uses 2nd messenger
Give and example of a Metabotrophic channel and what are they?
Open in response to hormones acting on other cell membrane receptor (uses 2nd messenger)
Examples of these types of ion channel are TRPs which are a type of non selective cation channels that gate both Na AND Ca
SECOND MESSENGER ACTIVATES TRP CHANNELS FOLLOWNING BINDING OF A HORMONE/DRUG ETC. TO A SEPERATE RECEPTOR
What happens when TRPV1 is activated?
Painful burning sensation
What are the agonists and antagonists for TRPV1 channels?
Agonist: Capsaicin
Antagonist: Capsazepine (Novartis)
What are the 3 main types of potassium channels?
Volatage gated potassium channels
Inwardly recitfying potassium channels IRCP
2 pore domain potassium channels
What are the agonists and antagonists of potassium channels?
Agonists: Openers lead to relaxation and vasodilation: Antihypertensives, anti-angina, Antiarrythmic
Antagonists: Sulphonylureas (anti-diabetic) blocks IRPC- stimulates insulin secretion
TEA-multiple sclerosis
Dendrotoxins-enhance release of acetylcholine
What are some of the disease related to potassium channels?
90 gene coding for the main subunit of K channels
Mutations in gene coding for K channels lead to dysfunction:
Neuronal system: alzheimers
Cardiac system: arrhythmias
Neonatal diabetes mellitus
Give 3 types of sodium channels?
Voltage gated
Receptor opertted sodium channels (metabotropic)
Ligand-gated sodium channels
Give the 3 types of calcium channels?
Voltage gated
Store operated calcium channels
IP3R/RyR intracellular calcium channels
What are calcium channels blockers used for and give an example of one?
Calcium channel blockers prevent calcium from entering cells of the heart and blood vessel walls, resulting in lower blood pressure.
L-type Ca channel blockers are used to treat hypertension
Amlodipine
Give and xample for plasma mem channel, Endoplasmic reticulum channel and mitochondrial channel?
PMC: voltage gated potassium channel (Kv)
ERC: RyR
MC: KATP (potassium channel, neonatal diabetes mellitus)
