Role of protein kinase Cζ and its adaptor protein p62 in voltage-gated potassium channel modulation in pulmonary arteries

Voltage-gated potassium (K-V) channels play an essential role in regulating pulmonary artery function, and they underpin the phenomenon of hypoxic pulmonary vasoconstriction. Pulmonary hypertension is characterized by inappropriate vasoconstriction, vascular remodeling, and dysfunctional K-V channels. In the current study, we aimed to elucidate the role of PKC zeta and its adaptor protein p62 in the modulation of K-V channels. We report that the thromboxane A 2 analog 9,11-dideoxy-11 alpha,9 alpha-epoxymethano-prostaglandin F-2 alpha methyl acetate (U46619) inhibited K-V currents in isolated mice pulmonary artery myocytes and the K-V current carried by human cloned K(V)1.5 channels expressed in Ltk(-) cells. Using protein kinase C (PKC)zeta(-/-) and p62(-/-) mice, we demonstrate that these two proteins are involved in the K-V channel inhibition. PKC zeta coimmunoprecipitated with K(V)1.5, and this interaction was markedly reduced in p62(-/-) mice. Pulmonary arteries from PKC zeta(-/-) mice also showed a diminished [Ca2+](i) and contractile response, whereas genetic inactivation of p62(-/-) resulted in an absent [Ca2+](i) response, but it preserved contractile response to U46619. These data demonstrate that PKC zeta and its adaptor protein p62 play a key role in the modulation of K-V channel function in pulmonary arteries. These observations identify PKC zeta and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension.