Transient inward current, delayed afterdepolarizations, and calmodulin kinase

Research output: Contribution to journalReview articlepeer-review

Abstract

Cardiac arrhythmias occur in a wide variety of conditions where increased intracellular Ca2+ is known to occur, including myocardial ischemia, cardiac glycoside toxicity, congestive heart failure, and excessive prolongation of action potential duration. The multifunctional Ca2+/calmodulin dependent protein kinase II (CaM kinase) is an important physiologic target for intracellular Ca2+ and regulates key control points for intracellular Ca2+ homeostasis, including L-type Ca2+ current, release and uptake of Ca2+ from the sarcoplasmic reticulum. Since CaM kinase is uniquely positioned to affect Ca2+ sensitive ionic currents and resultant arrhythmias, CaM kinase may also be an effective antiarrhythmic drug target. The transient inward current (Iti) triggers delayed afterdepolarizations, which are a likely cause of Ca2+ overload arrhythmias. The identity of Iti is controversial, but appears to result from different ionic currents depending on the experimental conditions. These currents are likely activated by intracellular Ca2+ because Iti always follows excessive intracellular Ca2+ concentrations ([Ca2+]i). The studies from our laboratory indicate that three different [Ca2+]i sensitive currents, which could contribute to Iti, are present in rabbit ventricular myocytes. These currents are the Na+/Ca2+ exchanger, the Ca2+ activated Cl- current, and the Ca2+ activated non-selective cation current. We also found that Iti was suppressed by CaM kinase inhibitory peptides in the presence of physiologic solutions. These data support the hypothesis: CaM kinase can augment Iti during clinically relevant conditions, which are associated with increased [Ca2+]i, and thus act as a proarrhythmic signaling molecule.

Original languageEnglish (US)
Pages (from-to)88-94
Number of pages7
JournalChinese Journal of Pharmacology and Toxicology
Volume15
Issue number2
StatePublished - Jan 1 2001
Externally publishedYes

Keywords

  • Action potentials
  • Arrhythmia
  • Ca-calmodulin dependent protein kinase
  • Delayed afterdepolarizations
  • Myocardium
  • Sodium-calcium exchanger
  • Transient inward current

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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