Ion Channels & Transporters Flashcards
Why are active transporters needed?
To create and maintain ion gradients
What is a uniport channel?
Transports one substance in one direction e.g. a selective ion channel
What is a symport channel?
Transports two different things in the same direction e.g. dopamine transporter
What is an antiport channel?
Transports two different things in two different directions e.g. sodium potassium ATPase
What does a Na+/K+ ATPase pump do?
Transports 3 sodium’s out and 2 potassium’s in every cycle, so in doing this there is a transfer of charge here so its electrogenic
Uses ATP in order to drive these ions across the membrane and there are various estimates that this enzyme could use around a third of the brains energy expenditure
What drugs inhibit Na+/K+ ATPase?
Cardiac glycosides digoxin
Ouabain
These drugs used for cardiac problems, they can increase the force of heart contraction but they don’t do this directly 🡪 what they do is lead to an increase in intracellular calcium but this is a secondary effect so by inhibiting the sodium potassium ATPase there is an increase in intracellular sodium levels and then this affects the sodium calcium co-transporter so that you end up with an increase in calcium🡪 it’s a secondary effect for what these are given for but with this enzyme being so important in the brain then you can get neurological and psychiatric effects
What is the structure of Na+/K+ ATPase?
Integral membrane protein, α & β (& γ) subunits
α 10 TM helices, mainly cytoplasmic
β single TM helix
Nucleotide-binding (N), phosphorylation (P) & actuator (A) domains
The important part is split into 3 domains🡪 Nucleotide-binding domain (N), phosphorylation domain (P) & actuator domain (A- causes the shape changes)
What do Ca2+ ATPases/pumps do?
Calcium ATPase’s basically maintain this gradient and there’s two different ones:
PMCA- plasma calcium membrane ATPase, pumps calcium out
SERCA pumps calcium into intracellular stores
What 3 things do voltage-gated channels require?
Need to contain these things:
voltage sensor (so it can respond to voltage changes),
selectivity filter (some kind of pore, that lets sodium through but not bigger things like sodium or potassium)
and gating mechanisms (closing the channel, keeping it closed during a refractory period and then letting it open again).
What are voltage-gated sodium channels?
Channels that carry the major inward current in action potentials
What is amino terminus?
The beginning of the protein
What is carboxy terminus?
The end of the protein
How many transmembrane domains are there?
4
How many helices are in each transmembrane domain?
6
What does it mean if transmembrane helcies are marked with a positive (+) symbol?
It is the axon voltage sensing helix
What do transmembrane helicies 5&6 contribute to?
The pore
5&6 form the central pore through which sodium ions go through
Na+ voltage gated channels are the drug target for what?
They are the target for anti-epileptic drugs e.g. lamotrigine
Lamotrigine binds within the membrane
It works by inhibiting cell pathways in the brain called sodium channels, which reduces the emission of chemicals glutamate and aspartate, two of the most important excitatory neurotransmitters in the brain
What is the difference betweem the absolute refractory period and the relative refractory period?
In the absolsute refractory period the channel is blocked from generating more action potentials whereas in the relative refracotry period it is possible to instigate another action potential but it is harder as the membrane is even more negative and so you would need an even stronger stimulus in order to begin an action potential
What are channel gating conformational changes?
When you’ve got a depolarisation the positions of the sensing helices change, theres major confirmational changes which open the channel on the inside allowing the influx of sodium there’s a kind of a selectivity pore so only sodium can get through it and not other ions
With the refractory period, there is then another part of the molecule which undergoes a confirmational change, kind of swings in and blocks the pore, and this takes a few seconds to rest before it can reset the channel
Why are Na+ channels important in terms of pharmacology?
Because there are lots of toxins that can target the channels
What syndrome are Na+ channels important in?
Epilepsy. There are various types of epilepsy that are caused by mutations of these Na+ gated channels
SCN1A – epilepsy, migraine, autism
SCN2A – epilepsy, autism, episodic ataxia
SCN3A – epilepsy
SCN9A – pain insensitivity & extreme pain disorder
What is the structure of voltage-gated potassium channels?
Similar to Na+ channels
4 α subunits, each with 6 TM helices, plus regulatory β subunits
What syndrome are K+ channels implicated in?
Epilepsy. Ataxia.
KCNQ2, KCNQ3, KCNMA1 associated epilepsy syndromes
KCNA1 associated with episodic ataxia type 1
What syndrome are K+ channels implicated in?
Epilepsy. Ataxia.
KCNQ2, KCNQ3, KCNMA1 associated epilepsy syndromes
KCNA1 associated with episodic ataxia type 1
What drugs target K+ channels and what do they treat?
Fampridine or Ampyra🡪 helps with walking in multiple sclerosis, not approved in England
Amiodarone–> helps with cardiac arrythmias
What voltage-gated channel is vital for neurotransmitter release?
Calcium voltage-gated channels
–> an influx of Ca2+ is vital for neurotransmitter release to occur
What is the structure of Ca2+ voltage-gated channels?
Four domains, each has 6 transmembrane helices and 5 & 6 in each one are pore forming ones that contribute to the pore
Beta subunits which associate with the channels and these are important to linking in with the downstream signalling pathways so interactions with various things
Towards the C terminus of the alpha subunits there is this domain which binds to the protein calmodulin, this is linked to signalling pathways –> calmodulin binds to calcium, gets activated, and that turns on specific kinase pathways within cells
They have polypeptides encoded by different genes so we can get all these different subunits which can be assembled in different ways and give you channels with different properties –> Lots of different genes and different channels with different properties which are expressed in different types of tissues and have different functions
What is the name of one important Ca2+ channel?
Ligand-activated Ca2+ channel
What is an example of a ligand-activated Ca2+ channels?
An example is IP3R –> a sugar with three phosphates on it. It diffuses to the intracellular sotres into the cytoplasm, turning on many different cell signalling pathways
What diseases are Ca2+ channels linked to?
Ataxia, Epilepsy
CACNA1A episodic ataxia type 2, SCA6 & familial hemiplegic migraine
CACNA1B myoclonus-dystonia syndrome
CACNA1F X-linked congenital stationary night blindness
CACNA1H childhood absence epilepsy
What are channel mutations called and what do they affect?
Channelopathies
Channel assembly and/or function
Pore permeability (increase or decrease)
Inactivation
What are ligand-gated channels?
A group of ion channels that are opened/closed in response to the binding of a chemical messenger (ligand).
They can bind extracellularly e.g. Glutamate, ACh pr GABA
Or
They can bind intracellularly e.g. Ca2+ on Ca2+-activated potassium channels
What is the primary type of ligand-gated channel?
Many neurotransmitter receptors are ligand-gated ion channels
What are sensory TRP channels?
Transient recetptor potential channels
They are non-selective cation (positively charged ion) channels
Can be gated by temperature, ligands etc
Implicated in PAIN and ITCH
What are TRP channels implicated in?
TRPA1- nociceptive pain, inflammatroy pain, headaches, migraines, itch
TRPM8- cold hypersensitivity, neuropathic pain, headaches, migraines, itch
TRPV1- neuropathic pain, inflammatory pain, itch
TRPV4- Mechanically-evoked pain, inflammaotry pain, neuropathic pain, visceral pain, itch, headache
