Week 8 Flashcards
(16 cards)
Animals produce ion channel blockers to paralyze prey. Examples of this are
- Dendrotoxin-I from the black mamba
- Apamin from the honey bee
What are the mechanisms of these blockers
- Dendrotoxin: Blocks Ca2+ channels, activates K+ channels
- Apamin: Same
What are the roles of ‘M’ and ‘H’ gates in Na+ channels
- M gates are in the middle on the channel and are closed at rest (open during inactivation)
- H gates are at the intracellular tip on the ion channel and close during inactivation (but are open at rest)
Describe the structure of the alpha subunit of Na+ channels
- 4 repeating domains
- Each domain has transmembrane spanning regions
- Transmembrane regions 5 and 6 are the bits that forms the pore
Ion channels are selective to a specific type of ion. How they do this is pretty nuts.
How does the K+ channel selective to K+ ions rather than, say, Na+ ions?
- K+ ions are bigger than Na+ ions
- The structure of the p loop is fairly rigid, causing K+ to shed its water molecules when entering the pore
- Both K+ and Na+ ions have the same number of water molecules attached to it
- The size of the pore is big enough to interact with the K+ ions, strip the water off etc. However, Na+ is NOT big enough to interact with surrounding carbonyls of the pore or to shed its water molecules completely etc
- This means it is not energetically favourable for Na+ to be in the channel
What is tetrodotoxin?
- Potent neurotoxin made by puffer fish,specifically an Na+ channel blocker
- Accumulates in the liver and ovaries of the puffer fish
What is the mechanism of action of TTX?
- Potently blocks the ability of neurons to conduct action potentials by blocking voltage-gated Na+ channels.
- It does this ONLY from the extracellular side of the membrane and blocks open or closed channels equally well
Does the term guanidinium moiety mean anything to you eh?
- The guanidinium moiety is a structure that is apart of the TTX molecule that enters the mouth of the Na+ channel
- Other parts of TTX then interact with the other amino acid residues around the entrance of the pore and generate high affinity bonds, blocking the channel!
Why does TTX not kill the puffer fish?
- Puffer fish Na+ channels (AND the ones found in the mammalian heart) are not blocked by TTX
- 4 P loops form the mouth of the Na+ channel (including the selectivity filter)
- Mutagenesis experiments revealed that various amino acid mutations within these p-loops can make the channel insensitive to TTX
How do local anaesthetics work?
Preventing nerve conduction through blocking Na+ channels
What is the relationship between LAs and pH?
- Typically they exist as weak bases and, at physiological pH, predominantly carry a positive charge
- The action of LA is strongly pH dependent, with LA activity being greatly reduced at an acidic pH
- QX-314 revealed that LAs preferentially block Na+ channels from an intracellular site.
- Thus, acidic pH reduces LA potency because it reduces the permeability of the membrane to an uncharged molecule (LAs more ionised in acidic pHs)
- Once inside the molecule, it is the charged form that blocks the channel
LAs fall into two structural classes: those with an amide group and those with an ester bond. EXAMPLE!
Amide: Lidocaine
Ester: Cocaine, Procaine
In terms of local anaesthetics, what is the
a) Hydrophobic pathway
b) Hydrophilic pathway
a) - Involves the movement of uncharged form of LAs across the membrane
- Once inside, the charged form blocks Na+ channels
- LAs can block in a non use-dependent way
b) - Ionisation of LAs at low pH cause reduced transport of LAs across the membrane
- Decreased efficacy occurs as a result
- Blocks by this pathway are use-dependent. I.e., the channel must be open for the block to occur
Just what the fuck is phenylalanine?
- A major determinant in the high affinity binding of LAs like lidocaine
- Allows local anaesthetics to bind to the site in the channel pore
What are some unwanted effects of LAs? (in different areas, any exceptions?)
- CNS - restlessness, tremor, confusion
- Cardiovascular - Myocardial depression, vasodilation
- Cocaine is an exception due to its ability to block noradrenaline uptake thus it can cause euphoria (CNS) and tachycardia and vasoconstriction (cardiovascular)
This is just some notes on the pharmacokinetics of LAs. Bit of an aids flash card really.
- Different LAs penetrate tissues at different rates.
- Lignocaine is rapidly absorbed with a medium duration of action
- LAs with an ester bond are degraded by plasma cholinesterase’s
- The effectiveness of LAs is often reduced in inflamed and infected tissues because of metabolic acidosis that lowers extracellular pH
What are some other uses of drugs that act on Na+ channels?
- As Anticonvulsants: Reducing the electrical of cell membrane, possibly through use-dependent blocking of sodium channels (e.g., Phenytoin)
- Class I Antidysrhythmic drugs: E.g., Quinidine
