AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol (October 2, 2003). doi:10.1152/ajpheart.00673.2003
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Submitted on July 16, 2003
Accepted on September 25, 2003

Phenotypic Differences in the Transient Outward K+ Current of Human and Canine Ventricular Myocytes: Insights into the Molecular Composition of Ventricular Ito

Fadi G Akar1, Richard C Wu1, Isabelle Deschenes1, Antonis A Armoundas1, Valentino Piacentino2, Steven R Houser2, and Gordon F Tomaselli1*

1 Cardiology, Johns Hopkins University, Baltimore, MD, USA
2 Physiology, Temple University, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: gtomasel{at}jhmi.edu.

The Ca2+-independent transient outward K+ current (Ito) plays an important electrophysiological role in normal and diseased hearts. However, its specific contribution to ventricular repolarization remains controversial, largely due to differences in its phenotypic expression and function across species. The dog is a frequently used model of human cardiac disease that exhibits altered functional expression of Ito. In order to better understand the relevance of electrical remodeling in dog to human disease, we studied the phenotypic differences in ventricular Ito between humans and dogs using electrophysiological, pharmacological, and protein-chemical techniques. The voltage-dependence and inactivation kinetics of human and canine Ito were examined under identical conditions. Several notable distinctions were elucidated, including a slower current decay, a more rapid recovery from inactivation, and a depolarizing shift of the steady-state inactivation relation in human compared to canine Ito. While recovery from inactivation of human Ito followed a monoexponential time-course, canine Ito recovered with biexponential kinetics. Pharmacological sensitivity to flecainide was markedly greater in human compared to canine Ito, and exposure to oxidative stress did not alter the inactivation kinetics of Ito in either species. Western blots of ventricular myocardium revealed immunoreactive bands specific for Kv4.3, Kv1.4, and KChIP2 in dog and man, but with notable differences in band sizes across species. We report for the first time major variations in the phenotypic properties of human and canine ventricular Ito despite the presence of the same {alpha} and subsidiary subunit immunoreactive proteins in both species. These data suggest that differences in the electrophysiological and pharmacological properties of Ito between humans and dogs are not caused by differential expression of the K channel subunit genes thought to encode Ito, but rather may arise from differences in the molecular structure and/or post-translational modification of these subunits as evidenced by the distinct differences in their apparent molecular weights.




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