Transient outward potassium current, 'Ito', 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,(fast)' (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 Ito 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, electro-physiological and pharmacological) for Kv4.2/4.3 alpha subunits underlying LV I-to,(fast) and Kv1.4 alpha 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 (Kv beta 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.