Preservation of cardiac function by prolonged action potentials in mice deficient of KCHIP2

Søren Grubb, Gary L. Aistrup, Jussi T. Koivumäki, Tobias Speerschneider, Lisa A. Gottlieb, Nancy A.M. Mutsaers, Søren Peter Olesen, Kirstine Calloe, Morten B. Thomsen*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K+ current (Ito,f) and with CaV1.2 to mediate the inward L-type Ca2+ current (ICa,L). Anesthetized KChIP2-/- mice have normal cardiac contraction despite the lower ICa,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVβ2 protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca2+ entry into the cell, thereby augmenting Ca2+-induced Ca2+ release. Ca2+ transients in disaggregated KChIP2-/- cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca2+-induced Ca2+ release event. We next functionally probed dyad structure, ryanodine receptor Ca2+ sensitivity, and sarcoplasmic reticulum Ca2+ load and found that increased temporal synchronicity of the Ca2+ release in KChIP2-/- cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on Ito,f and ICa,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2-/- mice.

Original languageEnglish (US)
Pages (from-to)H481-H489
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number3
DOIs
StatePublished - Aug 1 2015

Keywords

  • Action potentials
  • Calcium handling
  • Cardiac function
  • Ion channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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