Received for publication April 13, 2007.
Revised August 15, 2007.
Accepted for publication August 15, 2007.

Role of PKC and its adaptor protein p62 in KV channel modulation in pulmonary arteries

Abstract

Voltage-gated potassium (Kv) channels play an essential role in regulating pulmonary artery function and underpin the phenomenon of hypoxic pulmonary vasoconstriction. Pulmonary hypertension is characterised by inappropriate vasoconstriction, vascular remodelling and dysfunctional Kv channels. In the current study we aimed to elucidate the role of PKC and its adaptor protein p62 in the modulation of Kv channels. We report that the thromboxane A₂ analogue U46619 inhibited Kv currents in isolated mice pulmonary artery myocytes and the Kv current carried by human cloned Kv1.5 channels expressed in Ltk- cells. Using PKC-/- and p62-/- mice, we demonstrate that these two proteins are involved in the Kv channel inhibition. PKC co-immunoprecipitated with Kv1.5 and this interaction was markedly reduced in p62-/- mice. Pulmonary arteries from PKC-/- mice also showed a diminished [Ca²⁺]i and contractile response while genetic inactivation of p62-/- resulted in an absent [Ca²⁺]i response but preserved contractile response to U46619. These data demonstrate that PKC and its adapter protein, p62, play a key role in the modulation of KV channel function in pulmonary arteries. These observations identify PKC and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension.

Key words: Prostanoid, Ion channel regulation, Potassium, Protein Kinase C, Fluorescence techniques, Knockout