Ion Channels & Transporters

Question 1

Why are active transporters needed?

Answer 1

To create and maintain ion gradients

Question 2

What is a uniport channel?

Answer 2

Transports one substance in one direction e.g. a selective ion channel

Question 3

What is a symport channel?

Answer 3

Transports two different things in the same direction e.g. dopamine transporter

Question 4

What is an antiport channel?

Answer 4

Transports two different things in two different directions e.g. sodium potassium ATPase

Question 5

What does a Na+/K+ ATPase pump do?

Answer 5

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

Question 6

What drugs inhibit Na+/K+ ATPase?

Answer 6

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

Question 7

What is the structure of Na+/K+ ATPase?

Answer 7

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)

Question 8

What do Ca2+ ATPases/pumps do?

Answer 8

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

Question 9

What 3 things do voltage-gated channels require?

Answer 9

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).

Question 10

What are voltage-gated sodium channels?

Answer 10

Channels that carry the major inward current in action potentials

Question 11

What is amino terminus?

Answer 11

The beginning of the protein

Question 12

What is carboxy terminus?

Answer 12

The end of the protein

Question 13

How many transmembrane domains are there?

Answer 13

4

Question 14

How many helices are in each transmembrane domain?

Answer 14

6

Question 15

What does it mean if transmembrane helcies are marked with a positive (+) symbol?

Answer 15

It is the axon voltage sensing helix

Question 16

What do transmembrane helicies 5&6 contribute to?

Answer 16

The pore

5&6 form the central pore through which sodium ions go through

Question 17

Na+ voltage gated channels are the drug target for what?

Answer 17

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

Question 18

What is the difference betweem the absolute refractory period and the relative refractory period?

Answer 18

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

Question 19

What are channel gating conformational changes?

Answer 19

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

Question 20

Why are Na+ channels important in terms of pharmacology?

Answer 20

Because there are lots of toxins that can target the channels

Question 21

What syndrome are Na+ channels important in?

Answer 21

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

Question 22

What is the structure of voltage-gated potassium channels?

Answer 22

Similar to Na+ channels

4 α subunits, each with 6 TM helices, plus regulatory β subunits

Question 23

What syndrome are K+ channels implicated in?

Answer 23

Epilepsy. Ataxia.
KCNQ2, KCNQ3, KCNMA1 associated epilepsy syndromes
KCNA1 associated with episodic ataxia type 1

Question 24

What syndrome are K+ channels implicated in?

Answer 24

Epilepsy. Ataxia.
KCNQ2, KCNQ3, KCNMA1 associated epilepsy syndromes
KCNA1 associated with episodic ataxia type 1

Question 25

What drugs target K+ channels and what do they treat?

Answer 25

Fampridine or Ampyra🡪 helps with walking in multiple sclerosis, not approved in England

Amiodarone–> helps with cardiac arrythmias

Question 26

What voltage-gated channel is vital for neurotransmitter release?

Answer 26

Calcium voltage-gated channels

–> an influx of Ca2+ is vital for neurotransmitter release to occur

Question 27

What is the structure of Ca2+ voltage-gated channels?

Answer 27

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

Question 28

What is the name of one important Ca2+ channel?

Answer 28

Ligand-activated Ca2+ channel

Question 29

What is an example of a ligand-activated Ca2+ channels?

Answer 29

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

Question 30

What diseases are Ca2+ channels linked to?

Answer 30

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

Question 31

What are channel mutations called and what do they affect?

Answer 31

Channelopathies

Channel assembly and/or function
Pore permeability (increase or decrease)
Inactivation

Question 32

What are ligand-gated channels?

Answer 32

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

Question 33

What is the primary type of ligand-gated channel?

Answer 33

Many neurotransmitter receptors are ligand-gated ion channels

Question 34

What are sensory TRP channels?

Answer 34

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

Question 35

What are TRP channels implicated in?

Answer 35

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