Ion Channels as Drug Targets

Question 1

Why are ion channels important?

Answer 1

• communication
• cell membrane impervious to passive diffusion of ions
• ion channels create mechanism of change
• no. effector systems respond to changes in ion conc

Question 2

How do ion channels facilitate trans-membrane ionic flux?

Answer 2

• ions cannot diffuse across hydrophobic barrier

- channels provide polar environment for diffusion of ions

Question 3

What are the specialised functions of ion channels?

Answer 3

• mediate generation, conduction and transmission of electrical signals in NS
• control release of neurotransmitters and hormones
• initiate muscle contraction
• transfer small molecules between cells
• mediate fluid transport
• control growth and migration of cells

Question 4

How fast is conduction and why is it so fast?

Answer 4

• 10^8 ions/sec

- fast responses to stimuli

Question 5

How do ion channels act as catalysts?

Answer 5

• speed up fluxes
• not impart energy
• driving force provided by electrochemical potential

Question 6

What stochastic properties of channel opening are altered by gating?

Answer 6

• probability of channel shifting from open to closed

- length of time channel remains open

Question 7

What is ion channel gating?

Answer 7

• ligand gated
• voltage gated
• second messenger gating
• mechanical force gating
• temp gating

Question 8

How do we modulate ion channel activity?

Answer 8

• by exogenous agents
• ion channels susceptible to modulation at many different levels
• allows agents to have diff actions in diff tissues

Question 9

What are orthosteric ligands?

Answer 9

• act via endogenous ligand binding site
• replicate efficacy of agonist
• prevent ligand binding w/ no intrinsic efficacy (antagonist)

Question 10

What are allosteric modulation?

Answer 10

• +ve allosteric modulators
• amplifies endogenous ligands agonist effect
• enhances binding affinity/probability of channel opening or time channel is open for
• inactive in absence of orthosteric ligand
• induce conformational change in protein structure

Question 11

What are non-competitive antagonists?

Answer 11

• channel blockers = prevent channel opening
• several sites recognise different blockers
• blocks bind to several ligand gated ion channels

Question 12

What is protein modification?

Answer 12

• channels modification by tyrosine or serine
• alters membrane expression
• alters opening probability
• alter ligand binding

Question 13

How do ligand gated ion channels form basic wiring of the brain?

Answer 13

• glutamate - major excitatory neurotransmitter
• GABA - major inhibitory neurotransmitters
• acetylcholine - neurotransmitter in peripheral motor ns

Question 14

What are ligand gated channels?

Answer 14

• pentameric structure
• opening= allosteric effect
• channels remain open while ligand bound
• rapid clearance of ligand from synapse

Question 15

What are voltage gated ion channels?

Answer 15

• open when cell membrane is depolarised
• selective Na, K, Ca channel
• channel opening followed by slower inactivation

Question 16

What are the phases of Cardiac Action Potential?

Answer 16

0) Rapid depolarise, inward Na+ current
1) Partial depot, Na+ current inactivated
2) Plateau, inward Ca2+ current, outward K+ current
3) depolarisation, Ca2+ inactivates slow outward K+ current
4) Pacemaker potential maintained by Na+K+ATPase

Question 17

What is Epilepsy?

Answer 17

• seizure
• high frequency discharge by group of neurons caused by ligand gated and voltage gated ion channels
• detected by EEG
• partial seizure is localised
• generalised seizure

Question 18

What is anti epileptic therapy?

Answer 18

1) reducing excitability of cell membrane blocking voltage gated sodium channels
2) enhancing GABA mediated synaptic inhibition
3) inhibiting T type calcium channels

Question 19

What are local anaesthetics?

Answer 19

• weak base with ester linked aromatic group
• voltage dependent Na+ channel blockers
• block action potential propagation

Question 20

What are the mechanisms of action?

Answer 20

• act in cationic form
• penetrate nerve sheath and axon membrane unionised -> weak base
• inflamed tissue is acidic
• resistant to local anaesthetics
• block in small diameter nerve fibres

Question 21

What is use dependence?

Answer 21

• resting = closed state that prevails at normal resting potential
• activate = open state favoured by depolarisation
• anaesthetics only access and block channels when open
• more effect on rapidly firing neurons