Single channel kinetic analysis of the cAMP effect on IKs mutants, S209F and S27D/S92D

Channels
Emely ThompsonDavid Fedida

Abstract

The IKs current is important in the heart's response to sympathetic stimulation. β-adrenergic stimulation increases the amount of IKs and creates a repolarization reserve that shortens the cardiac action potential duration. We have recently shown that 8-CPT-cAMP, a membrane-permeable cAMP analog, changes the channel kinetics and causes it to open more quickly and more often, as well as to higher subconductance levels, which produces an increase in the IKs current. The mechanism proposed to underlie these kinetic changes is increased activation of the voltage sensors. The present study extends our previous work and shows detailed subconductance analysis of the effects of 8-CPT-cAMP on an enhanced gating mutant (S209F) and on a double pseudo-phosphorylated IKs channel (S27D/S92D). 8-CPT-cAMP still produced kinetic changes in S209F + KCNE1, further enhancing gating, while S27D/S92D + KCNE1 showed no significant response to 8-CPT-cAMP, suggesting that these last two mutations fully recapitulate the effect of channel phosphorylation by cAMP.

References

Jan 11, 2003·Science·Yi-Han ChenWei Huang
Feb 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Junko KurokawaRobert S Kass
May 26, 2004·Circulation·Chloé BellocqArthur A M Wilde
Aug 12, 2008·Channels·Coeli M B LopesDiomedes E Logothetis
Apr 28, 2010·The Journal of General Physiology·Jodene EldstromDavid Fedida
May 18, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yang LiJianmin Cui
Feb 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Daniel WerryDavid Fedida
Dec 3, 2014·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Jodene EldstromDavid Fedida
Jul 9, 2017·The Journal of General Physiology·Emely ThompsonDavid Fedida

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Citations

Sep 14, 2019·PloS One·Georg KuenzeJens Meiler
Jun 26, 2020·Frontiers in Physiology·Yundi WangDavid Fedida

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Methods Mentioned

BETA
transfection

Software Mentioned

GraphPad
pCLAMP
Digidata
Prism

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