Ion Channels as Drug Targets Flashcards
Why are ion channels important?
- communication
- cell membrane impervious to passive diffusion of ions
- ion channels create mechanism of change
- no. effector systems respond to changes in ion conc
How do ion channels facilitate trans-membrane ionic flux?
- ions cannot diffuse across hydrophobic barrier
- channels provide polar environment for diffusion of ions
What are the specialised functions of ion channels?
- 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
How fast is conduction and why is it so fast?
- 10^8 ions/sec
- fast responses to stimuli
How do ion channels act as catalysts?
- speed up fluxes
- not impart energy
- driving force provided by electrochemical potential
What stochastic properties of channel opening are altered by gating?
- probability of channel shifting from open to closed
- length of time channel remains open
What is ion channel gating?
- ligand gated
- voltage gated
- second messenger gating
- mechanical force gating
- temp gating
How do we modulate ion channel activity?
- by exogenous agents
- ion channels susceptible to modulation at many different levels
- allows agents to have diff actions in diff tissues
What are orthosteric ligands?
- act via endogenous ligand binding site
- replicate efficacy of agonist
- prevent ligand binding w/ no intrinsic efficacy (antagonist)
What are allosteric modulation?
- +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
What are non-competitive antagonists?
- channel blockers = prevent channel opening
- several sites recognise different blockers
- blocks bind to several ligand gated ion channels
What is protein modification?
- channels modification by tyrosine or serine
- alters membrane expression
- alters opening probability
- alter ligand binding
How do ligand gated ion channels form basic wiring of the brain?
- glutamate - major excitatory neurotransmitter
- GABA - major inhibitory neurotransmitters
- acetylcholine - neurotransmitter in peripheral motor ns
What are ligand gated channels?
- pentameric structure
- opening= allosteric effect
- channels remain open while ligand bound
- rapid clearance of ligand from synapse
What are voltage gated ion channels?
- open when cell membrane is depolarised
- selective Na, K, Ca channel
- channel opening followed by slower inactivation
What are the phases of Cardiac Action Potential?
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
What is Epilepsy?
- 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
What is anti epileptic therapy?
1) reducing excitability of cell membrane blocking voltage gated sodium channels
2) enhancing GABA mediated synaptic inhibition
3) inhibiting T type calcium channels
What are local anaesthetics?
- weak base with ester linked aromatic group
- voltage dependent Na+ channel blockers
- block action potential propagation
What are the mechanisms of action?
- 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
What is use dependence?
- 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
