Ion channel diversity Flashcards
why study ion channel diversity?
- important physiological roles e.g. muscle contraction
- can do a lot of things e.g. sense environment
- potential therapeutic targets
how are APs in heart generated and deactivated?
- depolarisation from influx of sodium ions
- plateau sustained by calcium ion influx
- opening of slow K+ channels to start repolarising
- opening of fast K+ channels to cause fast repolarization
what do regulators of excitability affect?
size, shape, frequency and pattern of APs
what’s the most diverse ion channel?
Potassium channel
what does the a-subunit of the potassium channel do?
forms majority of the channel
what does the B-subunit of the potassium channel do?
modulates a- subunit properties
what are the 4 types of K+ channel?
- calcium-activated
- inward rectifying
- 2- P domain
- voltage- gated
how does diversity arise in Na+ channels?
different accessory units
what are the 3 types of voltage gated Ca2+ channels?
- high voltage activated/ DHP sensitive - L type
- high voltage activated/ DHP insensitive
- low voltage activated- T-type
what 4 factors are used to differentiate ion channels?
- electrophysiology
- pharmacology
- modulation by regulatory molecules
- structure
what are the 3 ligand gated ion-channel alpha subunits?
Nicotinic Ach superfamily
glutamate family
P2X family
how many subunits does the nicotinic Ach superfamily have?
5- pentamer
how many subunits does the glutamate receptor family have?
4- tetramer
how many subunits does the P2X receptor family have?
3- trimer
what is the minimal motif requirement for a pore loop so it’s considered a channel?
S5- P- S6
what’s Kv channel made up of?
4 a-subunits (tetramer) forms functional channel
B-subunit- enhances cell surface expression, modulates channel gating (inactivation)
draw a voltage- gated potassium channel
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what part of the potassium channel has a voltage sensor?
S4
what is C-type gating?
localized inactivation
what is N-type gating?
particle inactivation
what speed is C-type gating?
slow
what speed is N-type gating?
rapid
what, evolutionarily are the most recent voltage-gated channels?
Na+ channels
what’s the main purpose of voltage gated sodium channels?
initiation and propagation of APs in excitable cells
what drugs target voltage gated sodium channels?
local anaesthetics, anticonvulsants and antiarrhythmics
what’s the structure of Na+ voltage gated channels?
pseudotetramer (4 TM domains)
do voltage gated sodium channels have rapid or slow activation?
rapid
what types of inactivation do voltage gated sodium channels have?
N and C
what do different Nav subunits have?
different biophysical properties
do Nav drugs tend to target 1 or many types of Nav channels?
many- hard to target just 1
what do drugs affecting Na 1.1 tend to treat?
epilepsy
what do drugs affecting Na 1.5 tend to treat?
cardiac arrythmias
what do drugs affecting Na 1.7,8,9 tend to treat?
Pain
what are the 2 types of Nav current?
Tetrotoxin sensitive
tetrotoxin resistant
what is a tetrotoxin sensitive current?
blocked by TTx in nM range rapid activation/ inactivation low activation threshold aromatic e.g. nerve/ skeletal muscle
what is a tetrotoxin resistant current?
blocked by tetrotoxin in micromolar range slow activation/ inactivation higher threshold polar e.g. cardiac/ sensory neurons
what has greater inward current flow, TTx sensitive or resistant?
sensitive
what peaks earlier TTx sensitive or resistant?
resistant
what do Nav TM B-subunits do (3)?
- modulate channel gating
- regulate cell surface expression
- function as cell adhesion molecules
where in Nav channel a-subunit do local anaesthetics bind?
TM 1,3 and 4
how many states are Nav channels in?
3
what are the 3 states of Nav channels?
closed- resting
open- activated
inactivated- closed
what can a mutation on Nav 1.7 cause?
Inherited Erythromelalgia
what does inherited erythromelalgia do?
hyper excitation of neurons
what are the symptoms of erythromelalgia
intense burning pain, redness, warmth
When do voltage-gated calcium channels open?
in response to cell depolarisation
in what direction does the calcium travel through voltage gated calcium channels?
inwards- influx
what do voltage gated calcium channels do that no other channels do?
convert electrical signals directly into biochemical work
e.g muscle contraction, gene expression etc.
what are the 5 types of Cav channels?
L type P/Q type R type N type T type
which a1- subunits do L-type have?
- 1
- 2
- 3
which a1- subunits do Q/P-type have?
2.1
which a1- subunits do N-type have?
2.2
which a1- subunits do R-type have?
2.3
which a1-subunits do T-type have?
- 1
- 2
- 3
what are L-type Cav channels used for?
skeletal/cardiac muscle contraction
secretion from glands
what are P/Q type channels used for?
transmitter release (CNS)
what are N- type channels used for?
transmitter release (PNS + CNS)
what are R- type channels used for?
transmitter release
what are T-type channels used for?
excitability
what else gives diversity to Cav channels (other than a-subunit)?
different B and a2delta
what Cav type do classical Cav antagonists target?
L-type
what are the 3 L-type channel blockers?
1,4- dihydropyradines
phenylalkylamines
benzothiazepines
what are 1,4 dihydropyradines?
anti- hypertensives
what are phenylalkylamines?
anti- arrhythmics
what are benzothiazepines?
anti- hypertensives and arrhythmics
what are the 4 main types of K+ channels?
Kv- voltage-gated
Kca- calcium gated
Kir -inward rectifiers
K2P- twin pore domain
what are the 2 voltage gated potassium channels?
delayed outward rectifiers
transcient A-type current
what are the 3 calcium gated potassium channels?
BKca- big conductance
IKca- intermediate conductance
SKca- small conductance
what do K+ channels in excitable cells do? (function) (6)
set RMP
stabilise MP
regulate repolarisation
terminate intense electrical activity
set time between spike intervals during repetitive AP firing
reduce potency of excitatory inputs on cells
what is RMP for most cells = ?
Ek (-90mV)
which K+ channels have 2 TMs ?
inward rectifier
which K+ channels have 4 TMs?
K2P
which K+ channels have 6TMs?
Kv, SKca, IKca
which K+ channels have 7TMs?
BKca
why is tetramer formation important?
enables channels have diversity
what are the 2 types of tetramer?
homomeric
heteromeric
what’s different between homoremic and heteroremic dimers?
homo- slower time to peak, larger depolarisation, less powerful repolarisation, small current
hetero- fast peak, smaller depolarisation, more powerful repolarisation, large current
what do delayed outward rectifiers do?
control AP duration
short neurons, long heart
what block outward rectifiers?
quaternary ammonium ions
what do transcient A-type currents do?
control AP interspike interval
if current is small- short interval
if current is large- long interval
what blocks transcient A-type currents?
dendrotoxins
what do Kcas do?
act to oppose calcium overload
AP repolarisation/after polarisation
are Kcas voltage sensitive and why?
no
they have no +ve AAs in S4
what activates Kcas?
IC calcium, binds to calmodulin on C-region
pore opens
calcium efflux
are inward rectifiers physiologically relevant?
no
what are the 2 types of Inward rectifier?
strong and weak
what do strong inward rectifiers do?
reduce threshold for excitation of neurons, skeletal and cardiac muscle
what do weak inward rectifers do?
more outward K+ current- reduces excitability
How does Kir affect Magnesium?
increases Mg2+, less K+ outward/efflux
stronger inward rectification
