Pharmacology - Ion Channels Flashcards
most abundant CATIONS in body:
sodium
potassium
calcium
most abundant ANIONS in body:
chloride
phosphate
fluoride
What are the Key Features and Properties of Ion Channel?
1) selective transmembrane pore
(molecular sieve/filter)
Charge & Size of the ions
-sodium channel will not permit potassium ions
-K+ channels more selective to K+ than Na+
- specific sensor for gating (open & close)
- involves confirmational change
Types of sensors or molecular switch
Membrane potential: Voltage-gated
neurotransmitter binding: Ligand gated
Temp & stretch: mechanosensitive
- Regulatory mechanisms
-“inactivation” control (in built)
Abundance & location (e.g. post synaptic density)
Modulation (G proteins, 2nd messengers, protein kinases)
Name the three key features and properties of ion channels?
- selective transmembrane pore (molecular sieve/filter)
- specific sensor for gating (open & close)
- involves conformational change - Regulatory mechanisms
how many subunits to form one channel?
4 subunits
Selectivity filter/molecular sieve
-align together to form a transmembrane pore
Contains positively charged aminoacids
-can move up & down in response to changes in membrane potential
Voltage-gated ion channels: voltage-sensing
what happens?
resting state > voltage sensors > depolarise > na+ inside cell
Voltage-gated ion channels- Inactivation loop
resting =
CLOSE Confirmation
Voltage-gated ion channels- Inactivation loop
Depolarised
OPEN-Active Confirmation
OPEN-Inactive Confirmation
blockage
Regulatory mechanisms
inactivation” control (in built)
An intracellular loop of the channel protein (e.g. “ball and chain”) blocks the pore after opening
How can voltage gated ion channel be influenced?
Other inorganic ions: Ex, calcium channel function can be influenced by Nickel ion
Neurotoxins: Toxins from various venoms (snake, spider and many others)
Drugs: Synthetic drugs
Voltage-gated ion channels- Sodium Channel
Neurotoxin blocks all three confirmation (open, close & inactivated)
e.g. tetrodotoxin from puffer fish
Voltage-gated ion channels- Sodium Channel
Lidocaine (local anaesthetic drug) prefer to act on open, inactivated state only
“use dependency”
USE DEPENDENCY
The ion channel blockade is dependent on the rate of action potential discharge (greater the frequency of firing, the greater the degree of blockade)
The following drug classes exhibit higher affinity for inactivated ion channels
anti-epileptics (phenytoin, carbamazepine, lamotrigine)
-anti-arrhythmic and local anaesthetics (disopyramide, procaine and lidocaine)
Voltage-gated ion channels- Calcium channel
Three types of calcium channels (differ in sensitivity and conductance)
Conductance > tiny > intermediate > large
Sensitivity > +ve to -70mV (low) > +ve to -10mV (high) > +ve to -10mV (high)
Calcium Channel - T-type
(transient)
Localisation = Pacemaker, nerves
Function = Contraction, neurotransmitter release
Drugs = Gabapentin, pregabalins (inhibit T-type calcium channel and neurotransmitter release)
Drug use = Epilepsy, neuropathic pain
Calcium Channel - N-type
(neuronal)
Localisation= Nerve terminus
Function = Neurotransmitter release
Drugs = -w-conotoxin (Zicotinide, synthetic analogue)
Drug use = Chronic severe pain
Why use intrathecal administration in calcium channels?
to block nociceptive nerves in spinal card, inhibiting neurotransmitters release
Calcium channels - L-type
(Long-lasting)
Localisation = Nerve terminus
Function = Cardiac & smooth muscles
Drugs = Smooth muscle: dihydropyridines, such as nifedipine, amlodipine
Cardiac cells: phenylalkylamines, such as verapamil
Both: benzothiazepines, such as diltiazem
Drug use = Blood pressure, Arrhythmia, Angina, Stroke
Voltage-gated ion channels- Potassium Channel
Some potassium channels modulated by
intracellular ligands: e.g. Intracellular Ca2+ activated potassium channels
G proteins: e.g. Muscarinic (M2 )receptor-Gbg-IK in cardiac pacemaker cells
Ligand-gated ion channels (nicotinic Ach receptor)
N & C terminus are located extracellular
Extracellular ligand binding site
S2 transmembrane domain forms the pore lining
5 different subunits attach to form a pentamer
e.g. nicotinic Ach receptor (2 a + b + d + e)- alpha units contain Ach binding pocket, i.e 2 Ach molecule binding required for receptor activation
Examples of neurotransmitter and its channels?
Acetylcholine Nicotinic AchR
ATP P2X
5-HT 5HT-3
Glutamate AMPA, NMDA, kainate
GABA GABAA receptors
Ligand-gated cation channels
Cation channels (Na+) – nicotinic Ach, glutamate, 5HT, P2X
» Depolarisation»_space; Excitatory
Ligand-gated anion channels
Anion channel (Cl-): GABA»_space; GABAA ICl »_space; Hyperpolarisation»_space; Inhibitory
What type of channel has a non-competitive antagonism / allosteric modulation?
Ligand-gated cation channels
Glutamate NMDA receptor
Ligand-gated anion channels
what is the process to get to inhibitory?
anion channel (Cl-) : GABA»_space; GABAa ICl > Hyperpolarisation > Inhibitory
reduced neuronal excitability
What are the advantages of Allosteric drugs?
offers a novel pharmacological options of “fine-tuning” receptor function
intensify a weakened hormone/ NT signal caused by localised deficit
Clinically safer drugs with enhanced selectivity and reduced liability for receptor tolerance and/or desensitation
