KV channels Flashcards
how many KV channels are there in the human genome
over 70
what do KV channels contribute to
control of cell volume
control of membrane potential and cell excitability
secretion of salts, hormones and neurotransmitters
what can KV channels be regulated by
hormones and transmitters
voltage across membrane
conc of Ca2+ or ATP in cytoplasm
kinase and phosphatases
G-proteins
what do KV channels respond to
electrochemical gradient (missing the voltage sensor)
what are KV responsible for
shaping of the AP
in native cells, what are the 2 main types of KV
inactivating (‘A’) type
non-inactivating (delayed recifier)
inactivation of KV channels (ball and chain model)
‘A’ type K+ channels display rapid inactivation following opening - deletion of residued 6 to 46 caused currents which displayed no inactivation
inactivation caused by first 20 AAs - which forms compact hydrophobic/charged surfct domain (the ball) following 50-60 AA form the ‘chain’
basically when a cell is being stimulated, ball/chain loops and blocks channel which inactivates it
what is ion selectivity of K channels determined by
carbonyl backbone groups of the TVGYG motif in the P loop
what is the ball and chain model often reffered to as
N-type inactivation (involved N-terminus structure)
what constitues the receptor for the inactivation ball
a set of AAs in the S4-S5 loop (near the internal channel mouth)
what can addition of b-subunits do
induce fast inactivation
what is the function of calcium-activated K+ channels modulated by
Ca2+
what are the sybtypes of calcium-activated K+ channels
large conductance (~250pS) K+ channels (aka BK)
KCa or Maxi-K channels
intermediate conductance channels (IK - 60-100pS)
small conductance channels (SK - </=20pS)
in neurons, what are SK channeks responsible for
slow afterhyperpolarisation (AHP) observed after AP discharges
where are maxi-K channels expressed
ubiquitously except the heart
what do maxi-K channels do within neurons
help shape APs and regulate transmitter release
what do maxi-K channels do in smooth muscle
help regulate contractility and tone
how are maxi-K channels opened
they are voltage-dependant - so opening is controlled by transmembrane voltage (gated by depolarisation)
what is the activation voltage of K+ channels dependant on
intracellular CA2+ concentratoon
as the Ca2+ conc increases, the channel required less electrical energy to open
describe the structure of the maxi-K channnel
extra transmembrane domain at N-terminal region, resulting in exoplasmic NH2 terminus
long COOH terminus region
what encodes a Maxi-K a subunit
a single gene (slo)
what happens when b1-b4 interact with Maxi-K subunit
alter Ca2+ sensitivity and voltage, activation kinetics and pharmacology
what is required for he b subunit modulation of channels
S0/N-terminal domain
what does the a subuniy primary sequence contain
possible phosphorylation sites and additions of splice insertions adds more - resulting in channels differentially regulated by protein kinases/phosphatases
where are Maxi-K channels abundant
mammalian CNS and smooth muscle
what domains does maxi-k have
voltage-gated and ligand-gated
what is the typical voltage sensor within the Kv channel
S4 region acting as voltage sensor (as maxi-K does not possess a voltage sensor)
what does the ligand-gated mechanism involve
specialized structures present in the C-terminal region of the protein
what do RCK (regulator of conductance of K+) domains contribute to
binding of an intracellular ligand
where are hydrophobic segments found
in the C-terminus
what does pressure on the RCK lead do
a conformational change (when Ca2+ is bound)
what determines the Ca2+ sensitivity of the channel
tail domain of alpha subunit - region between S9 and S10 - contains a series of negatively charged (D) residues
what happens when there is mutations in the region between S9 and S10
effect high affinity sensing of calcium
what does increasing intracellular calcium lead to
increases the opening force on the channel gates (bc it has bound to these sites) - which leads to increased channel opening
why is the maxi-K an important feedback system for calcium entry in many cell types
because of its sensitivity to calcium
what does maxi-K play an important role in
timing of bursts of APs - also contributes to AHP
maxi-K role in vascular reactivity
they induce hyperpolarization and balance the effects of excessive vasoconstriction - open in response to local elevations of Ca2+ and relax smooth muscle (close Ca2+ channels)
what correlates to hypertension
loss of B1 subunit
(no B1 subunit - maxi-K is less Ca2+ sensitive, and so get increased arterial tone and BP)
how do maxi-K channels provide a mechanism for cochlear hair frequency tuning
various splice varients of a subunit, in combination with b subunits and CaV channels - determines frequency to which each hair cell responds - frequency encoding in hearing
how to maxi-K channels contribute to vascular smooth muscle relaxation
Ca release by CICR via ryanodine receptors causes local increase in [Ca]i, this activates BK channels which gives K efflux, which hyperpolarizes the membrane which closes CaV that gave the initial depolarization and contraction - and so the smooth muscle relaxes
where are maxi-K channels present at high levels
axon terminals, somas and dendrites
what happens when you block maxi-K channels
AP is broadened, AHP is diminished
how many loops are required to make a functional K+ channel
4
what does ratification mean
structural elements in channel which ensure movement of channel in only one direction
explain the two TM domain
one pore family consist of the inward rectifiers - these channels conducy K+ currents more in the inward direction than the outward and help set RMP
explain the four TM domain
two pore family are weak inward rectifiers - most abundant class of K+ channels - act as ‘background’ channels and help set RMP
what are TREK1 channels
signal integrators
what do TREK1 channels respond to
many inputs of mechanical deformation
- internal pH reduction
- heat
- intracellular lipids
- fatty acids
what happens when TREK1 channels are activated
increased channel opening and hyperpolarization of RMP
how does inhibition of TREK1 occur
phosphorylation of intracellular sites via PKC and PKA
what can open TREK1
various votile and gaseous anaesthetic agents
where is human TREK1 highly expressed
in the brain
functions of TREK1 (as seen in mice)
- decreased sensitivity to anaesthetics
- more sensitive to brain ischemia and epilepsy
- loss of neuroprotection from polyunsaturated fatty acids
- mood regulation (anti-depressant)
what happens when TREK1 opens in presynaptic terminals
closes CaV channels and decreases release of neurotoxic glutamate
what hppens when TREK1 opens in postsynaptic sites
hyperpolarising of the cell and increased NMDA receptor Mg2+ block - reduced excitotoxicity
give examples of potassium channel openers (KCOs)
cromakalim
pinacidil
minoxidil
diazoxide
what is diazoxide occasionally used to do
decrease insulin secretion from beta cells
KCOs relax
smooth muscle
when GTP is bound to G proteins…
K+ channels open
what is the activity of G-protein terminated by
intrinsic GTPase activity of the G-protein itself - converting GTP to GDP
