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Differential modulation of Kv4.2 and Kv4.3 channels by calmodulin-dependent protein kinase II in rat cardiac myocytes

¹Universidad de Valladolid y Consejo Superior de Investigaciones Científicas, Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular, Facultad de Medicina, Valladolid; and ²Universidad del País Vasco, Facultad de Farmacia, Departamento de Fisiología, Bilbao, Spain

Submitted 26 December 2005 ; accepted in final form 18 April 2006

In this work we have combined biochemical and electrophysiological approaches to explore the modulation of rat ventricular transient outward K⁺ current (I_to) by calmodulin kinase II (CaMKII). Intracellular application of CaMKII inhibitors KN93, calmidazolium, and autocamtide-2-related inhibitory peptide II (ARIP-II) accelerated the inactivation of I_to, even at low [Ca²⁺]. In the same conditions, CaMKII coimmunoprecipitated with Kv4.3 channels, suggesting that phosphorylation of Kv4.3 channels modulate inactivation of I_to. Because channels underlying I_to are heteromultimers of Kv4.2 and Kv4.3, we have explored the effect of CaMKII on human embryonic kidney (HEK) cells transfected with either of those Kv-subunits. Whereas Kv4.3 inactivated faster upon inhibition of CaMKII, Kv4.2 inactivation was insensitive to CaMKII inhibitors. However, Kv4.2 inactivation became slower when high Ca²⁺ was used in the pipette or when intracellular [Ca²⁺] ([Ca²⁺]_i) was transiently increased. This effect was inhibited by KN93, and Western blot analysis demonstrated Ca²⁺-dependent phosphorylation of Kv4.2 channels. On the contrary, CaMKII coimmunoprecipitated with Kv4.3 channels without a previous Ca²⁺ increase, and the association was inhibited by KN93. These results suggest that both channels underlying I_to are substrates of CaMKII, although with different sensitivities; Kv4.2 remain unphosphorylated unless [Ca²⁺]_i increases, whereas Kv4.3 are phosphorylated at rest. In addition to the functional impact that phosphorylation of Kv4 channels could cause on the shape of action potential, association of CaMKII with Kv4.3 provides a new role of Kv4.3 subunits as molecular scaffolds for concentrating CaMKII in the membrane, allowing Ca²⁺-dependent modulation by this enzyme of the associated Kv4.2 channels.

transient outward current; cardiac electrophysiology; immunoprecipitation

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