Transient outward potassium current, 'I_to', phenotypes in the mammalian left ventricle: Underlying molecular, cellular and biophysical mechanisms

At least two functionally distinct transient outward K⁺ current (I_to) phenotypes can exist across the free wall of the left ventricle (LV). Based upon their voltage-dependent kinetics of recovery from inactivation, these two phenotypes are designated 'I_to,fast' (recovery time constants on the order of tens of milliseconds) and 'I_to,slow' (recovery time constants on the order of thousands of milliseconds). Depending upon species, either I_to,fast, I_to,slow or both current phenotypes may be expressed in the LV free wall. The expression gradients of these two I_to phenotypes across the LV free wall are typically heterogeneous and, depending upon species, may consist of functional phenotypic gradients of both I_to,fast and I_to,slow and/or density gradients of either phenotype. We review the present evidence (molecular, biophysical, electrophysiological and pharmacological) for Kv4.2/4.3 α subunits underlying LV I_to,fast and Kv1.4 α subunits underlying LV I_to,slow and speculate upon the potential roles of each of these currents in determining frequency-dependent action potential characteristics of LV subepicardial versus subendocardial myocytes in different species. We also review the possible functional implications of (i) ancillary subunits that regulate Kv1.4 and Kv4.2/4.3 (Kvβ subunits, DPPs), (ii) KChIP2 isoforms, (iii) spider toxin-mediated block of Kv4.2/4.3 (Heteropoda toxins, phrixotoxins), and (iv) potential mechanisms of modulation of I_to,fast and I_to,slow by cellular redox state, [Ca²⁺]_i and kinase-mediated phosphorylation. I_to phenotypic activation and state-dependent gating models and molecular structure-function relationships are also discussed.