Lizzy - ion channel diversity Flashcards
difference between neuron and heart action potentials.
graphs.
draw out in notes
main types of ion channels?
ion gated and ligand gated.
others that dont fit, ie aquaporins
what are the types of voltage gated Ca channels?
L type:
- high voltage activated
- DHP sensitive
High voltage activated
DHP insensitive
T type:
- low voltage activated
what were ion channels classified due to at first?
Electrophysiology – ion selectivity, voltage-dependence, current kinetics
Pharmacology – agonist/antagonist activity of specific drugs
Modulation by regulatory molecules – Ca2+, Gβγ, ATP
Structure – topology of pore-forming subunits, auxiliary subunits, amino acid sequence
describe the voltage gated K channels.
- most primitive
- 6 TMD
- intracellular N and C terminus
- voltage sensor on S4 coupled to the pore region to allow opening.
- pore region between S5 and S6, membrane dipping/P loop. contains selectivity filter
- for a functional channel we need 4x a subunits, the pore loops form the lining of the channel.
- B subunits enhances cell surface expression and modulate channel gating (inactivation)
describe TM B subunits in Nav channels.
- short intracellular tail and long extracellular head.
- different to Kav B unit.
- modulates channel gating
- can function autonomously independent of the pore forming part of channel, has role as cell adhesion molecules.
- regulate cell surface expression.
describe B subunits in Kav channels
- B subunits enhances cell surface expression and modulate channel gating (inactivation)
- 4 TMD
- linked to voltage sensor?
describe the Ca voltage channels
- 1 B and 1 a2delta
- B subunit is an intracellular protein
- a2delta transmembrane glycoproteins
- gamma subunits.
only gamma1 associated with Cav, ignore it basically.
describe the voltage sensing region
- S4
- positively charged arginine or lysine every 3/4 residues within S4 of voltage gated channels.
- when a V gated channel opens charged amino acids move through membrane electric field, coupling electrical work to the process of opening.
slide about ball and chain?
no idea m8
N-type – N-terminal amino acids (~20) act as “ball” to plug channel pore.
Some βs fulfil similar function.
C-type – Constriction of outer mouth of pore
describe Na voltage gated channels and their roles.
Most recent voltage-gated channel in evolutionary terms
Essential role in initiation &
propagation of APs in excitable cells.
Important targets for Local anaesthetics, anticonvulsants & antiarrhythmic agents
Development Nav-selective drugs for tmt of pain
what are the types of Nav currents?
TTx-s (Tetrodotoxin-sensitive)
Blocked by TTx in nM range (1-100 nM)
Rapid activation/inactivation
Low threshold of activation
E.g. skeletal muscle, nerve
rapid on rate and peak
open at smaller depolarisations
TTx-r (Tetrodotoxin-resistant)
Blocked by µM TTx (1-10 µM).
Slower activation/inactivation
Activate at more depolarised potentials
E.g. cardiac muscle, sensory neurons
slower, less amplitude
where do TTX/STX bind on an a subunit in a Na channel?
TMD1 on the extracellular loop between 5/6
? idk what this is for probs ignore it
describe where local anaesthetics bind?
S6 domain I, III & IV
S6 are critical for inactivation of the pore.
lock the channel into an inactivated state.
when do cav channels open?
when the cell membrane is depolarised.
describe low voltage activated ca channels.
small conductance
fast activation/inactivation
which type of Ca channel has no specific target?
L type, selective to dihydropyridines
which is the only low voltage activated type of Ca channel?
T
describe the opening of types of channels during an action potential.
T type channels open as you initiate an AP, peak at around -20mv.
during the AP as the membrane depolarises there is a big influx of Ca through L type channels.
how is further diversity added to Ca channels?
B and a2delta subunits are added. further differentiation.
what are uses for L type antagonists?
treatment of cardiac arrhythmias & hypertension
what are uses for N type channel blockers?
novel treatments for neuropathic pain
what are gabapentinoids?
target calcium channel auxiliary subunits, a2delta 1/2
treatment for epilepsy and neuropathic pain
name 3 L type channel blockers
1,4-dihydropyridines (DHPs) e.g. nifedipine – anti-hypertensive
Phenylalkylamines (PAAs) e.g. verapamil – anti-arrhythmic
used in the heart
Benzothiazepines (BTZs) e.g. diltiazem – anti-arrhythmic/hypertensive
heart/smooth muscle
all bind to S6 in TM III & IV
DHP only S5 on TM III
interfere with gating of the channel
what is the most diverse group of channels?
K+
how does a resting membrane potential come about?
dominated by ionic species with greatest permeability across membrane.
For most cells = K+
what are the roles of K channels?
Set r.m.p.
STABILISE membrane potential - bring it closer to EK (≈ -96 mV) and further away from the firing threshold (≈ -55 mV) for AP.
Ensure AP repolarisation phase is fast.
Terminate periods of intense electrical activity.
Set the time between spike intervals during repetitive AP firing.
Reduce potency of excitatory inputs on cells.
what are the main families of K channels?
Kv - Delayed outward rectifiers + transient A-type current
Kca - calcium activated, split into two: small conductance (IKca, SKca) large conductance (BKca)
Kir - inward rectifiers
K2P - twin/tandem pore domain
??
what are the structural differences in K channels?
Kir - only 2 TMs
K2P - 2 P loops, 4 TMD
only need a dimer to get 4 P loops
Kv, SKca & IKca - 6 TMD
BKca - 7TMD
what are the types of Kv channels?
- Delayed Rectifiers
Control of AP duration
AP SHORT if current on quickly (nerve/sk. muscle)
AP LONG if current on slowly (heart)
Pharmacology: blocked by quaternary ammonium ions, e.g. TEA
- Transient A-type currents
Control of AP interspike interval (timing of repetitive spikes)
Interspike interval SHORT if current small
Interspike interval LONG if current large
Pharmacology: blocked by 4-AP (4-amino-pyridine); Dendrotoxin
how can Kv channels increase diversity?
Kv channels need to form tetromers to form a channel pore.
can form heteromers over homomers, interact with a subunits from different channels.
different properties from both parent channels.
describe the structure of BKca channels
7TMD
S4 segment is voltage sensitive.
C terminal domain has a calcium bowl that binds calcium ions.
both are required to open
what is the function of BKca?
ALL KCa channels – oppose Ca2+ overload from repetitive stimulation.
- AP occurs, depolarisation due to Na
- Ca influx
- opens BKca so influx of K which repolarises the cell membrane.
BKCa coupled with Cav2.2 (N-type) - mediate fast after-hyperpolarisation in neurons & inhibition NT release.
BKCa channels – single α subunit, diverse properties dependent on association with different β subunits!!
describe SKca and IKca
Voltage-insensitive
Activated by low [Ca2+]i (‹1.0 μM)
S4 not voltage sensitive.
no direct binding to C tail, bind via ca binding protein -calmodulin
Function: Regulation of AP firing frequency
AP repolarisation & after-
hyperpolarisation in vertebrate
neurons. E.g. SKCa coupled to
L-type Cav in sk. muscle.
describe inward rectifier K channels
Structure
:2 TM domains – equivalent to S5–P-S6 of other K+ channels
Several subfamilies identified
Physiological roles:
Stabilise r.m.p. near to EK.
Strong rectifiers (e.g. Kir2.1 and 3.1) reduce threshold for excitation in neurons, skeletal & cardiac muscle.
Weak rectifiers (e.g. Kir1.1 and 6.1) pass more outward current, mediate K+ fluxes across epithelia. In excitable cells, activation reduces excitability.
efflux to stabilise inside of cell
