+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

A long QT mutation substitutes cholesterol for phosphatidylinositol-4,5-bisphosphate in KCNQ1 channel regulation

A long QT mutation substitutes cholesterol for phosphatidylinositol-4,5-bisphosphate in KCNQ1 channel regulation

Plos one 9(3): E93255

Phosphatidylinositol-4,5-bisphosphate (PIP2) is a cofactor necessary for the activity of KCNQ1 channels. Some Long QT mutations of KCNQ1, including R243H, R539W and R555C have been shown to decrease KCNQ1 interaction with PIP2. A previous study suggested that R539W is paradoxically less sensitive to intracellular magnesium inhibition than the WT channel, despite a decreased interaction with PIP2. In the present study, we confirm this peculiar behavior of R539W and suggest a molecular mechanism underlying it. COS-7 cells were transfected with WT or mutated KCNE1-KCNQ1 channel, and patch-clamp recordings were performed in giant-patch, permeabilized-patch or ruptured-patch configuration. Similar to other channels with a decreased PIP2 affinity, we observed that the R243H and R555C mutations lead to an accelerated current rundown when membrane PIP2 levels are decreasing. As opposed to R243H and R555C mutants, R539W is not more but rather less sensitive to PIP2 decrease than the WT channel. A molecular model of a fragment of the KCNQ1 C-terminus and the membrane bilayer suggested that a potential novel interaction of R539W with cholesterol stabilizes the channel opening and hence prevents rundown upon PIP2 depletion. We then carried out the same rundown experiments under cholesterol depletion and observed an accelerated R539W rundown that is consistent with this model. We show for the first time that a mutation may shift the channel interaction with PIP2 to a preference for cholesterol. This de novo interaction wanes the sensitivity to PIP2 variations, showing that a mutated channel with a decreased affinity to PIP2 could paradoxically present a slowed current rundown compared to the WT channel. This suggests that caution is required when using measurements of current rundown as an indicator to compare WT and mutant channel PIP2 sensitivity.

Please choose payment method:

(PDF emailed within 1 workday: $29.90)

Accession: 051152608

Download citation: RISBibTeXText

PMID: 24681627

Related references

Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome. Circulation Research 96(7): 730-739, 2005

Cholesterol modulates ion channels via down-regulation of phosphatidylinositol 4,5-bisphosphate. Journal of Neurochemistry 112(5): 1286-1294, 2010

Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5-bisphosphate. Journal of General Physiology 146(5): 357-374, 2015

KCNE1-KCNQ1 osmoregulation by interaction of phosphatidylinositol-4,5-bisphosphate with Mg2+ and polyamines. Journal of Physiology 588(Pt 18): 3471-3483, 2010

Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. Journal of Neuroscience 25(43): 9825-9835, 2005

Synergistic modulation of KCNQ1/KCNE1 K(+) channels (IKs) by phosphatidylinositol 4,5-bisphosphate (PIP2) and [ATP]i. Cellular Signalling 27(7): 1457-1468, 2015

Complex regulation of the TRPC3, 6 and 7 channel subfamily by diacylglycerol and phosphatidylinositol-4,5-bisphosphate. Cell Calcium 43(5): 506-514, 2008

Phosphatidylinositol 4,5-bisphosphate and ATP-sensitive potassium channel regulation: a word of caution. Diabetes 49(9): 1409-1412, 2000

The phenotype of a KCNQ1 mutation depends on its KCNE partners: is the cardiac slow delayed rectifier (IKs) channel more than a KCNQ1/KCNE1 complex?. Heart Rhythm 4(12): 1542-1543, 2007

Regulation of ROMK1 channel by protein kinase A via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America 96(10): 20-5, 1999

Mutation analysis of potassium channel genes KCNQ1 and KCNH2 in patients with long QT syndrome. Chinese Medical Journal 116(9): 1333-1335, 2003

Biophysical characteristics of a new mutation on the KCNQ1 potassium channel (L251P) causing long QT syndrome. Canadian Journal of Physiology and Pharmacology 81(2): 129-134, 2003

Congenital long QT syndrome caused by the F275S KCNQ1 mutation: mechanism of impaired channel function. Biochemical and Biophysical Research Communications 380(1): 127-131, 2009

Structural determinants of phosphatidylinositol 4,5-bisphosphate (PIP2) regulation of BK channel activity through the RCK1 Ca2+ coordination site. Journal of Biological Chemistry 289(27): 18860-18872, 2014