Pharmacology - Ion Channels

Question 1

most abundant CATIONS in body:

Answer 1

sodium
potassium
calcium

Question 2

most abundant ANIONS in body:

Answer 2

chloride
phosphate
fluoride

Question 3

What are the Key Features and Properties of Ion Channel?

Answer 3

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+

2. 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

3. Regulatory mechanisms
   -“inactivation” control (in built)
   Abundance & location (e.g. post synaptic density)
   Modulation (G proteins, 2nd messengers, protein kinases)

Question 4

Name the three key features and properties of ion channels?

Answer 4

1. selective transmembrane pore (molecular sieve/filter)
2. specific sensor for gating (open & close)
   - involves conformational change
3. Regulatory mechanisms

Question 5

how many subunits to form one channel?

Answer 5

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

Question 6

Voltage-gated ion channels: voltage-sensing
what happens?

Answer 6

resting state > voltage sensors > depolarise > na+ inside cell

Question 7

Voltage-gated ion channels- Inactivation loop
resting =

Answer 7

CLOSE Confirmation

Question 8

Voltage-gated ion channels- Inactivation loop
Depolarised

Answer 8

OPEN-Active Confirmation

Question 9

OPEN-Inactive Confirmation

Answer 9

blockage

Question 10

Regulatory mechanisms

Answer 10

inactivation” control (in built)
An intracellular loop of the channel protein (e.g. “ball and chain”) blocks the pore after opening

Question 11

How can voltage gated ion channel be influenced?

Answer 11

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

Question 12

Voltage-gated ion channels- Sodium Channel

Answer 12

Neurotoxin blocks all three confirmation (open, close & inactivated)
e.g. tetrodotoxin from puffer fish

Question 13

Voltage-gated ion channels- Sodium Channel

Answer 13

Lidocaine (local anaesthetic drug) prefer to act on open, inactivated state only

“use dependency”

Question 14

USE DEPENDENCY

Answer 14

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)

Question 15

Voltage-gated ion channels- Calcium channel

Answer 15

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)

Question 16

Calcium Channel - T-type
(transient)

Answer 16

Localisation = Pacemaker, nerves

Function = Contraction, neurotransmitter release

Drugs = Gabapentin, pregabalins (inhibit T-type calcium channel and neurotransmitter release)

Drug use = Epilepsy, neuropathic pain

Question 17

Calcium Channel - N-type
(neuronal)

Answer 17

Localisation= Nerve terminus

Function = Neurotransmitter release

Drugs = -w-conotoxin (Zicotinide, synthetic analogue)

Drug use = Chronic severe pain

Question 18

Why use intrathecal administration in calcium channels?

Answer 18

to block nociceptive nerves in spinal card, inhibiting neurotransmitters release

Question 19

Calcium channels - L-type
(Long-lasting)

Answer 19

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

Question 20

Voltage-gated ion channels- Potassium Channel

Answer 20

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

Question 21

Ligand-gated ion channels (nicotinic Ach receptor)

Answer 21

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

Question 22

Examples of neurotransmitter and its channels?

Answer 22

Acetylcholine Nicotinic AchR
ATP P2X
5-HT 5HT-3
Glutamate AMPA, NMDA, kainate
GABA GABAA receptors

Question 23

Ligand-gated cation channels

Answer 23

Cation channels (Na+) – nicotinic Ach, glutamate, 5HT, P2X
» Depolarisation&raquo_space; Excitatory

Question 24

Ligand-gated anion channels

Answer 24

Anion channel (Cl-): GABA&raquo_space; GABAA ICl &raquo_space; Hyperpolarisation&raquo_space; Inhibitory

Question 25

What type of channel has a non-competitive antagonism / allosteric modulation?

Answer 25

Ligand-gated cation channels
Glutamate NMDA receptor

Question 26

Ligand-gated anion channels
what is the process to get to inhibitory?

Answer 26

anion channel (Cl-) : GABA&raquo_space; GABAa ICl > Hyperpolarisation > Inhibitory

reduced neuronal excitability

Question 27

What are the advantages of Allosteric drugs?

Answer 27

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