Molecular diversity of the repolarizing voltage‐gated K + currents in mouse atrial cells

1 Voltage‐clamp studies on atrial myocytes isolated from adult and postnatal day 15 (P15) C57BL6 mice demonstrate the presence of three kinetically distinct Ca 2+ ‐independent, depolarization‐activated outward K + currents: a fast, transient outward current ( I to,f ), a rapidly activating, slowly inactivating current ( I K,s ) and a non‐inactivating, steady‐state current ( I ss ). The time‐ and voltage‐dependent properties of I to,f , I K,s and I ss in adult and P15 atrial cells are indistinguishable. 2 Pharmacological experiments reveal the presence of two components of I K,s : one that is blocked selectively by 50 μM 4‐aminopyridine (4‐AP), and a 4‐AP‐insensitive component that is blocked by 25 mM TEA; I ss is also partially attenuated by 25 mM TEA. There are also two components of I K,s recovery from steady‐state inactivation. 3 To explore the molecular correlates of mouse atrial I K,s and I ss , whole‐cell voltage‐clamp recordings were obtained from P15 and adult atrial cells isolated from transgenic mice expressing a mutant Kv2.1 α subunit (Kv2.1N216Flag) that functions as a dominant negative, and from P15 atrial myocytes exposed to (1 μM) antisense oligodeoxynucleotides (AsODNs) targeted against Kv1.5 or Kv2.1. 4 Peak outward K + current densities are attenuated significantly in atrial myocytes isolated from P15 and adult Kv2.1N216Flag‐expressing animals and in P15 cells exposed to AsODNs targeted against either Kv1.5 or Kv2.1. 5 Analysis of the decay phases of the outward currents evoked during long (5 s) depolarizing voltage steps revealed that I K,s is selectively attenuated in cells exposed to the Kv1.5 AsODN, whereas both I K,s and I ss are attenuated in the presence of the Kv2.1 AsODN. 6 In P15 and adult Kv2.1N216Flag‐expressing atrial cells, mean ± s.e.m. I K,s and I ss densities are also significantly lower than in non‐transgenic atrial cells. In addition, pharmacological experiments reveal that the TEA‐sensitive component I K,s is selectively eliminated in P15 and adult Kv2.1N216Flag‐expressing atrial cells. 7 Taken together, the results presented here reveal that both Kv1.5 and Kv2.1 contribute to mouse atrial I K,s , consistent with the presence of two molecularly distinct components of I K,s . In addition, Kv2.1 contributes to mouse atrial I ss .