Molecular aspects of adrenergic modulation of the transient outward current

Transient outward channels have a different impact on action potential configuration in small mammals compared to large mammals. Small mammals depend primarily on I-to1 for repolarization, while in larger animals I-to1 only indirectly determines action potential duration by setting the level of the plateau. Transient outward channel expression and distribution also differ between animal species. Nevertheless, the primary protein sequence of the underlying Kv1.4, Kv4.2 and Kv4.3 alpha(1)-subunits displays remarkably high levels of amino acid identity. Transient outward channels are subject to alpha- and beta-adrenergic regulation, mainly decreasing I-to1. However, adrenergic stimulation is also an important determinant of transient outward channel downregulation in cardiac disease. Adrenergic stimulation of PKA as well as PKC leads to an inhibition of 1,, 1, which has been correlated with phosphorylation of the Kv1.4, Kv4.2 and Kv4.3 alpha(1)-subunits. Calmodulin-dependent kinase II, on the other hand, has been shown to be involved in an increase of I-to1. Comparison of Kv1.4, Kv4.2 and Kv4.3 primary amino acid sequences demonstrates a strong conservation of (potential) phosphorylation sites between different species, despite the fact that I-to1 has a different effect on action potential configuration in mammalian species. (c) 2006 European Society of Cardiology. Published by Elsevier B.V.