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

The transient outward potassium current (I-to) is an important repolarizing current in the mammalian heart. I-to is regulated by adrenergic stimulatio n; however, the effect of agonists on this current, and consequently the ac tion potential duration and profile, is variable. An important source of th e variability is the difference in the channel genes that underlie I-to. Th ere are two subfamilies of candidate genes that are likely to encode I-to i n 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 Kv 4.3) further complicates the effect of alpha -adrenergic modulation of card iac I-to. In the human ventricle, hKv4.3 is the predominant gene underlying I-to. 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 th e COOH-terminus with a consensus protein kinase C (PKC) site. We used heter ologous expression of hKv4.3 splice variants and studies of human ventricul ar myocytes to demonstrate that alpha -adrenergic modulation of I-to occurs through a PKC signaling pathway and that only the long splice variant (hKv 4.3-L) is modulated via this pathway. Only a single hKv4.3-L monomer in the tetrameric I-to channel is required to confer sensitivity to phenylephrine (PE). Mutation of the PKC site in hKv4.3-L eliminates alpha -adrenergic mo dulation of the hKv4.3-encoded current. The similar, albeit less robust, mo dulation of human ventricular I-to by PE suggests that hKv4.3-L is expresse d in a functional form in the human heart.