Abstract
Gradients of the fast transient outward K+ current (Ito,f) contribute to heterogeneity of ventricular repolarization in a number of species. Cardiac Ito,f levels and gradients change notably with heart disease. Human cardiac Ito,f appears to be encoded by the Kv4.3 pore-forming α-subunit plus the auxiliary KChIP2 β-subunit while mouse cardiac Ito,f requires Kv4.2 and Kv4.3 α-subunits plus KChIP2. Regional differences in cardiac Ito,f are associated with expression differences in Kv4.2 and KChIP2. Although Ito,f was reported to be absent in mouse ventricular cardiomyocytes lacking the Kv4.2 gene (Kv4.2-/-) when short depolarizing voltage pulses were used to activate voltage-gated K+ currents, in the present study, we showed that the use of long depolarization steps revealed a heteropodatoxin-sensitive Ito,f (at ~40% of the wild-type levels). Immunohistological studies further demonstrated membrane expression of Kv4.3 in Kv4.2-/- cardiomyocytes. Transmural Ito,f gradients across the left ventricular wall were reduced by ~3.5-fold in Kv4.2-/- heart, compared to wild-type. The Ito,f gradient in Kv4.2-/- hearts was associated with gradients in KChIP2 mRNA expression while in wild-type there was also a gradient in Kv4.2 expression. In conclusion, we found that Kv4.3-based Ito,f exists in the absence of Kv4.2, although with a reduced transmural gradient. Kv4.2-/- mice may be a useful animal model for studying Kv4.3-based Ito,f as observed in humans.
Highlights
The fast transient outward potassium current (Ito,f) modulates action potential profile, Ca2+ handling, contractility and hypertrophy in cardiomyocytes [1, 2]
Voltage-dependent K+ currents in mouse cardiomyocytes are generated by Kv4.2/Kv4.3, Kv1.4, Kv1.5 and Kv2.1-encoded channels [4, 14, 16, 17, 21,22,23,24,25,26,27]
Cardiomyocytes from Kv4.2-/- mouse hearts could be fit well with tri-exponential functions and we found no differences in either the amplitudes or decay kinetics of the Ik,slow1, Ik,slow2 and Isus components between the groups (Fig 1B and Table 1)
Summary
The fast transient outward potassium current (Ito,f) modulates action potential profile, Ca2+ handling, contractility and hypertrophy in cardiomyocytes [1, 2]. Ito,f is developmentally regulated [3] and its levels are invariably reduced in heart disease. Kv4.3-Encoded K+ Current in Mouse Cardiomyocyte species [4, 5] and these gradients are often altered in diseased hearts [6]. The pore-forming αsubunits of Ito,f channels are comprised of Kv4.2 and Kv4.3 in rodents [7], but apparently only Kv4.3 in humans [8]. In both case, they form oligomeric complexes with the obligatory auxiliary subunit KChIP2, as well as either DPP6 or DPP10 [7]. While the Ito,f gradient in humans and dogs are linked to regional differences in KChIP2 expression [4, 9], the basis for regional differences in mouse Ito,f is not clear with studies concluding that either Kv4.2 or KChIP2 or both underlie the transmural gradient [10]
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