Dynamics of the late Na+ current during cardiac action potential and its contribution to afterdepolarizations

Balazs Horvath, Tamas Banyasz, Zhong Jian, Bence Hegyi, Kornel Kistamas, Peter P. Nanasi, Leighton T Izu, Ye Chen-Izu

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The objective of this work is to examine the contribution of late Na+ current (INa,L) to the cardiac action potential (AP) and arrhythmogenic activities. In spite of the rapidly growing interest toward this current, there is no publication available on experimental recording of the dynamic INa,L current as it flows during AP with Ca2+ cycling. Also unknown is how the current profile changes when the Ca2+-calmodulin dependent protein kinase II (CaMKII) signaling is altered, and how the current contributes to the development of arrhythmias. In this study we use an innovative AP-clamp Sequential Dissection technique to directly record the INa,L current during the AP with Ca2+ cycling in the guinea pig ventricular myocytes. First, we found that the magnitude of INa,L measured under AP-clamp is substantially larger than earlier studies indicated. CaMKII inhibition using KN-93 significantly reduced the current. Second, we recorded INa,L together with IKs, IKr, and IK1 in the same cell to understand how these currents counterbalance to shape the AP morphology. We found that the amplitude and the total charge carried by INa,L exceed that of IKs. Third, facilitation of INa,L by Anemone toxin II prolonged APD and induced Ca2+ oscillations that led to early and delayed afterdepolarizations and triggered APs; these arrhythmogenic activities were eliminated by buffering Ca2+ with BAPTA. In conclusion, INa,L contributes a significantly large inward current that prolongs APD and unbalances the Ca2+ homeostasis to cause arrhythmogenic APs.

Original languageEnglish (US)
Pages (from-to)59-68
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume64
DOIs
StatePublished - Nov 2013

Keywords

  • Action potential
  • Calcium
  • Cardiac
  • Late Na current
  • Myocyte
  • Na channel

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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