BMS303 Lecture 4

  • Created by: Mollie
  • Created on: 17-01-18 00:16
There are beta subunits for Cav, Kv and CL- channels. In what ways are they responsible for regulating alpha subunits?
How the channel gates, its voltage dependence, its changes and trafficking
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In cardiac action potential: the fast depolarisation phase is due to the opening of the ?? channels, the plateau phase is due to the slow opening of the ?? channels and the repolarization is due to the opening of the ?? channels.
In cardiac action potential: the fast depolarisation phase is due to the opening of the Nav channels, the plateau phase is due to the slow opening of the Cav channels and the repolarization is due to the opening of the Kv channels.
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Why would the loss of a Kv cardiac channel result in a prolonged QT (LQT)?
Because the loss of a Kv channel will result in slower repolarisation
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The Ikr is current from KCNH2 channel is a voltage dependent inward rectification channel found on cardiac myocytes, it is carried by hERG1 channels and has its own accessory subunit. Why can't this current be experimentally recorded?
While it is a delayed rectifier channel its activation and inactivation is rapid in how compares to other K+ channels but slower than Na channels
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How many transmembrane domains are there in MinK/KCNE1?
One
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What was observed when KCNE1 was over expressed in oocytes?
The oocytes went from having very small K currents to having very large K currents. They found that while KCNE1 is not a K channel it was upregulating KCNQ1 which was already there
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Does the expression of KCNQ1 alone or KCNQ1 + KCNE1 (Iks current) produce faster current activation?
KCNQ1 alone produces faster current activation but a plateau is reached very quickly and the current is very small, while KCNE1 alone produces no current
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What does the relative shift to the right seen in a graph recording current produced by KCNE1 and KCNQ1 together compared to KCNQ1 alone mean about potential cells with both proteins need to reach a certain current?
This shows that a more positive potential is needed to achieve the same relative current as KCNQ1 alone
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While LQT syndrome is fairly asymptomatic until the patients teenage years or during exercise - possibly related to hormone levels, what are some symptoms that do characterize the disease
arrhythmias, synscope, sudden death
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There are both autosomal dominant and recessive forms of LQT syndrome, how many different forms of LQT syndrome are known of all together?
12, between 1:10,000 - 1;15,000 are affected by LQT syndrome
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An example of a QT interval which is too long is 0.54s as this is longer than usual every now and then there will be a mismatch in the cardiac cycle. What is the normal length of a QT interval at rest?
0.36s
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What effect on Iks currents (from KCNQ1 channels) do these mutations in KCNE1 proteins have; V47F, L51H, D76N, W87R?
They all greatly decrease Iks currents
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What are the 3 potential mechanisms of action impacted by mutations in KCNE1 proteins?
Gating, trafficking and regulation
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Which KCNE1 mutation results in smaller Iks currents similar to when KCNQ1 is expressed alone and thus demonstrates/provides supporting evidence for the role of KCNE1 in gating KCNQ1?
L51H
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What was observed about KCNE1 localisation when the L51H KCNE1 mutant was expressed in permeablised and non permeabilized cells compared to WT KCNE1 proteins using antibodies and FLAG?
In WT non permeabilized KCNE1 expression seen around cell's periphery & WT permeabilized cells expressed it around the periphery (mostly PM) whereas LH15 mutant expression was at high conc below the PM as it can't traffick to the membrane
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Results from a co-localisation study of the L51H KCNE1 mutant using a resident ER marker calnexin showed WT proteins co localising well in the ER but there is also lots of KCNE1 at the cell membrane, what did the L51H mutant cell show?
The mutant appeared to be trapped in the ER with only a small amount of the protein in the cytosol so it can't traffic KCNQ1 to the plasma membrane
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Why does the L51H KCNE1 mutation lead to problems with repolarization in myocytes?
Because KCNE1 becomes mostly trapped in the ER so insufficient KCNQ1 channels are trafficked to the plasma membrane and thus Iks currents are considerably smaller
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True or false, evidence has indicated that KCNE1 protein mutations such as L51H also impairs K+ transport via Kv1.4 channels?
False, when WT and L51H KCNE1 mutants were compared the mutation showed it had no impact on Kv1.4 transport
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What neurotransmitter is responsible for acting on beta-2 adrenoreceptors via G-proteins to increase cAMP which activates Iks and increases the density of the currents thus increasing heart rates
noradrnaline
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Why does the increase in Iks current density result in increased heart rate?
There is faster repolarisation when channels are open for longer (earlier?). This impact of the SNS is important as it reduces the duration of the cardiac cycle for which time intervals in the heart must accomodate
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Why do many LQT patients die playing sports or jumping into cold water?
These activities would result in the SNS trying to increase their heart rates which would increase their risk of arrhythmias and sudden cardiac death syndrome as Iks currents are responsible for mediating this and theirs struggle to
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When an increase in heart rate is no longer required how is the KCNQ1/KCNE1 complex inactivated to return heart rate to normal?
Protein phosphatase 1 (PP1) dephosphorylates the complex which inactivates it so heart rate returns to normal
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What impact on currents does adding cAMP and OA (a PP1 inhibitor) to cells with KCNQ1 proteins but not KCNE1 proteins?
They had little effect on currents in this condition but in cells with KCNQ1 and KCNE1 adding these increased the current compared to the control demonstrating the importance of KCNE1 in the response of ventricular myocyte stimulation by the SNS
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W87R KCNE1 mutants do show an increase in Iks currents in the presence of cAMP and have no impact on regulation so what impairment is seen in this genotype?
There are fewer channels in the membrane so they show smaller Iks and their overall response to cAMP is lower (although single channel response is the same)
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D76N KCNE1 mutations are very strong mutations with few channels in the PM and thus small K currents and show no sensitivity to CAMP. What happens when sufferers exercise?
They struggle to increase repolarisation, putting them at risk of sudden cardiac death in situations in which their heart rate has to increase
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Give 2 examples of beta subunits which are known to regulate K channels other than the KCNE family.
Kvbeta, KChIPS, KChAP, 14-3-3 proteins, AKAPAs
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Other cards in this set

Card 2

Front

In cardiac action potential: the fast depolarisation phase is due to the opening of the ?? channels, the plateau phase is due to the slow opening of the ?? channels and the repolarization is due to the opening of the ?? channels.

Back

In cardiac action potential: the fast depolarisation phase is due to the opening of the Nav channels, the plateau phase is due to the slow opening of the Cav channels and the repolarization is due to the opening of the Kv channels.

Card 3

Front

Why would the loss of a Kv cardiac channel result in a prolonged QT (LQT)?

Back

Preview of the front of card 3

Card 4

Front

The Ikr is current from KCNH2 channel is a voltage dependent inward rectification channel found on cardiac myocytes, it is carried by hERG1 channels and has its own accessory subunit. Why can't this current be experimentally recorded?

Back

Preview of the front of card 4

Card 5

Front

How many transmembrane domains are there in MinK/KCNE1?

Back

Preview of the front of card 5
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