Modulation of Kv4-encoded K⁺ currents in the mammalian myocardium by neuronal calcium sensor-1

Voltage-gated K⁺ channels are multimeric proteins, consisting of four pore-forming α-subunits alone or in association with accessory subunits. Recently, for example, it was shown that the accessory Ky channel interacting proteins form complexes with Kv4 α-subunits and modulate Kv4 channel activity. The experiments reported here demonstrate that the neuronal calcium sensor protein-1 (NCS-1), another member of the recoverin-neuronal calcium sensor superfamily, is expressed in adult mouse ventricles and that NCS-1 co-immunoprecipitates with Kv4.3 from (adult mouse) ventricular extracts. In addition, co-expression studies in HEK-293 cells reveal that NCS-1 increases membrane expression of Kv4 α-subunits and functional Kv4-encoded K⁺ current densities. Co-expression of NCS-1 also decreases the rate of inactivation of Kv4 α-subunit-encoded K⁺ currents. In contrast to the pronounced effects of Kv channel interacting proteins on Kv4 channel gating, however, NCS-1 co-expression does not measurably affect the voltage dependence of steady-state inactivation or the rate of recovery from inactivation of Kv4-encoded K⁺ currents. Taken together, these results suggest that NCS-1 is an accessory subunit of Kv4-encoded I_to,f channels that functions to regulate I_to,f density in the mammalian myocardium.