AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 281: H2518-H2527, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 6, H2518-H2527, December 2001

Mechanism of alpha -adrenergic regulation of expressed hKv4.3 currents

Sunny S. Po*, Richard C. Wu*, George J. Juang, Wei Kong, and Gordon F. Tomaselli

Division of Cardiology, Department of Medicine, and Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland 21205

The transient outward potassium current (Ito) is an important repolarizing current in the mammalian heart. Ito is regulated by adrenergic stimulation; however, the effect of agonists on this current, and consequently the action potential duration and profile, is variable. An important source of the variability is the difference in the channel genes that underlie Ito. There are two subfamilies of candidate genes that are likely to encode Ito in the mammalian heart: Kv4 and Kv1.4; the predominance of either gene is a function of the species, stage of development, and region of the heart. The existence of different isoforms of the Kv4 family (principally Kv4.2 or Kv4.3) further complicates the effect of alpha -adrenergic modulation of cardiac Ito. In the human ventricle, hKv4.3 is the predominant gene underlying Ito. Two splice variants of human Kv4.3 (hKv4.3) are present in the human ventricle; the longer splice variant contains a 19-amino acid insert in the COOH-terminus with a consensus protein kinase C (PKC) site. We used heterologous expression of hKv4.3 splice variants and studies of human ventricular myocytes to demonstrate that alpha -adrenergic modulation of Ito occurs through a PKC signaling pathway and that only the long splice variant (hKv4.3-L) is modulated via this pathway. Only a single hKv4.3-L monomer in the tetrameric Ito channel is required to confer sensitivity to phenylephrine (PE). Mutation of the PKC site in hKv4.3-L eliminates alpha -adrenergic modulation of the hKv4.3-encoded current. The similar, albeit less robust, modulation of human ventricular Ito by PE suggests that hKv4.3-L is expressed in a functional form in the human heart.

potassium channels; adrenergic receptors; heterologous expression; site-directed mutagenesis; protein kinase C; phorbol esters

* Authors contributed equally to this study.




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