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 language | English (US) |
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Pages (from-to) | 88-94 |
Number of pages | 7 |
Journal | Chinese Journal of Pharmacology and Toxicology |
Volume | 15 |
Issue number | 2 |
State | Published - Jan 1 2001 |
Externally published | Yes |
Keywords
- Action potentials
- Arrhythmia
- Ca-calmodulin dependent protein kinase
- Delayed afterdepolarizations
- Myocardium
- Sodium-calcium exchanger
- Transient inward current
ASJC Scopus subject areas
- Toxicology
- Pharmacology