Ion Channels as Drug Targets

Question 1

What cells may ion channels be found in?

Answer 1

Excitable cells, eg neurons, cardiac myocytes, vascular smooth muscle and neuroendocrine cells

Non-excitable cells, eg lymphocytes, kidney and gut

Question 2

Give four basic features of ligand-gated ion channels

Answer 2

They are ionotropic receptors

They are triggered to open by binding of a specific ligand such as 5-HT, NMDA, or ATP

They have a selectivity filter that discriminates between ions

They are classified based on size: trimers, tetramers and pentamers

Question 3

Give some basic features of ion channels

Answer 3

They are integral, pore-forming, membrane proteins that allow ion flow according to electrochemical gradient.

Question 4

What type of proteins are ion channels?

Answer 4

Integral, PORE-FORMING MEMBRANE proteins

Question 5

What is the function of ion channels?

Answer 5

Allow ion flow according to electrochemical gradient

Question 6

What type of EXCITABLE cells are ion channels found in? (list 4)

Answer 6

Neurons
Cardiac myocytes
Vascular smooth muscle
Neuroendocrine cells

Question 7

What type of NON-EXCITABLE cells are ion channels found in? (list 3)

Answer 7

Lymphocytes
Kidney
Gut

Question 8

What are the two main classes of ion channels?

Answer 8

1) ligand-gated

2) voltage-gated

Question 9

Give the main features of a LIGAND-gated ion channel

Answer 9

IONOTROPIC receptors that are triggered to open by the binding of a SPECIFIC ligand

Question 10

Give some examples of ligands that may trigger ligand-gated ion channels to open

Answer 10

5-HT
NMDA
ATP

Question 11

What allows ion channels to discriminate between ions?

Answer 11

SELECTIVITY FILTER

Question 12

Ion channels may be classified based on size. Which family are:

1) pentamers
2) tetramers
3) trimers

Answer 12

1) cys-loop receptor (nicotinic ACh) superfamily
2) glutamate receptor family
3) P2X receptor family

Question 13

Give some examples of receptors in the Cys-loop receptor (nicotinic ACh) superfamily.

Answer 13

Nicotinic ACh receptor
5-HT3 receptor
GABA(A) receptor
Glycine receptor
ZAC

Question 14

What drugs are targeted against the following members of the Nicotinic Ach (cys-loop receptor) superfamily? What sort of ligand are each of these drugs?

1) 5-HT3
2) GABA(A)
3) Nicotinic

Answer 14

1) 5-HT3 - antagonist - alosteron
2) GABA - agonists - benzodiazepines (BZDs)
3) nicotinic - partial agonists - varenidine

Question 15

Alosteron is a drug targeted against a specific type of ligand-gated ion channels. Which type?

Answer 15

The nicotinic ACh (cys-loop receptor) superfamily: it is an antagonist against 5-HT3 receptors

Question 16

Which proteins do benzodiazepines target, and how?

Answer 16

GABA ion channels - they act as allosteric agonists

Question 17

What drugs are targeted against members of the glutamate receptor family?

Answer 17

the NMDA receptor ANTAGONIST, memantine

Question 18

No drugs are in clinical use for which ligand-gated ion channel family?

Answer 18

the P2X receptor family

Question 19

Against which receptor is MEMANTINE targeted, and what is its clinical use?

Answer 19

It is an NMDA receptor ANTAGONIST, and is clinically used for Alzheimer’s disease

Question 20

What are NMDA receptors?

Answer 20

1) members of the tetrameric glutamate receptor family

2) non-selective cation channels that allow calcium entry

Question 21

How can Alzheimer’s disease be treated through targeting ligand-gated ion channels?

Answer 21

Excessive glutamate activity is neurotoxic in Alzheimer’s disease.
NMDA receptors are a member of the glutamate receptor family of ion channels; they are selective cation channels that allow calcium entry.
The NMDA receptor antagonist MEMANTINE can therefore be used to treat Alzheimer’s disease.

Question 22

How can the activity of NMDA receptors be measured?

Answer 22

Whole-cell recording

Question 23

What is MEMANTINE?

Answer 23

A non-competitive, low-affinity NMDA receptor antagonist

Question 24

What is MEMNATINE’s clinical use?

Answer 24

An antineurotixic to combat excessive activity of glutamate receptors important in the pathology of Alzheimer’s disease
…slows the onset of symptoms

Question 25

Calcium channels can be drug targets in which 3 main (general) areas?

Answer 25

1) cardiovascular system 2) chronic pain 3) epilepsy

Question 26

Which type of calcium channels are involved in cardiac PHARMACOLOGY?

Answer 26

L-type calcium channels (aka dihydropyridine receptors)

Question 27

What is another term for L-type calcium channels?

Answer 27

Dihydropyridine receptors

Question 28

L-type calcium channels have the binding sites for dihydropyridines (DHPs). What is the nature of most dihydropyridines?

Answer 28

Most DHPs are calcium channel BLOCKERS, aka calcium antagonists (e.g. nifedipine)

Question 29

Give an example of an L-type calcium channel blocker

Answer 29

Nifedipine (a dihydropyridine, DHP)

Question 30

Calcium channels are present in both the heart and vascular smooth muscle. How are calcium channel blockers tissue-sensitive?

Answer 30

Dihydropyridines, DHPs (eg nifedipine) are NEUTRAL, and preferentially effective in vascular smooth muscle Phenylalkylamines (eg verapamil) are CHARGED and are preferentially active in the heart

Question 31

Which type of calcium blocker is preferentially active in vascular smooth muscle? Give an example

Answer 31

Dihydropyridines (DHPs), eg. nifedipine ...these are NEUTRAL

Question 32

Which type of calcium blocker is preferentially effective in the heart? Give an example.

Answer 32

Phenylalkylamines, e.g. verapamil ...these are CHARGED

Question 33

Phenylalkylamines (eg verapamil) can only bind to the calcium channel when it is in which state?

Answer 33

OPEN state

Question 34

Dihydropyridines (eg nifedipine) are able to block calcium channels when they are in WHICH state(s)?

Answer 34

OPEN/ INACTIVATED states

Question 35

How do Phenylalkylamines differ from Dihydropyridines in their binding to calcium channels?

Answer 35

Phenylalkylamines are charged drugs that only block calcium channels in their OPEN state. Therefore their blocking action is USE-DEPENDENT and the block is most effective in cell in which calcium channels are most active

Question 36

What do Phenylalkylamines require in order to exert their effects? Therefore which cell type (and disorder) are they useful in treating?

Answer 36

The calcium channels to be in their open state, and an action potential. CARDIAC MYOCYTES rapidly fire APs, therefore they are good targets for phenylalkylamines. Used to treat CARDIAC DYSRHYTHMIAS

Question 37

What can verapamil be used to treat?

Answer 37

Cardiac dysrhythmias

Question 38

What is NIFEDIPINE, and what can it be used to treat?

Answer 38

A NEUTRAL drug (dihydropyridine) that binds channels in their open or inactive state, and impose a VOLTAGE-DEPENDENT BLOCK upon depolarisaton. As vascular smooth muscle tone is controlled by depolarisation, it is used for HYPERTENSION to relax smooth muscle of arterioles. Nifedipine will have some effects on the heart but preferential for the smooth muscle

Question 39

What tissue does nifedipine act on?

Answer 39

Preferentially on the smooth muscle of arterioles (but has some effects on the heart)

Question 40

How can calcium channels be targeted to treat chronic pain?

Answer 40

Analgesic drug based on w-connotoxin (ZICONOTIDE) blocks presynaptic N-type calcium channels in the dorsal horn to prevent release of nociceptive neuropeptides, eg substance P

Question 41

What is ziconotide, and what is it used for?

Answer 41

An analgesic drug based on w-connotoxins that blocks presynaptic N-type calcium channels in the dorsal horn to inhibit release of nociceptive neuropeptides to treat CHRONIC NEUROPATHIC PAIN

Question 42

How is ziconotide administered?

Answer 42

as an intrathecal injection