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Role of Protein Kinase C and Its Adaptor Protein p62 in Voltage-Gated Potassium Channel Modulation in Pulmonary Arteries

Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain

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 and its adaptor protein p62 in the modulation of K_V channels. We report that the thromboxane A₂ analog 9,11-dideoxy-11,9-epoxymethano-prostaglandin F₂ methyl acetate (U46619 [GenBank] ) inhibited K_V currents in isolated mice pulmonary artery myocytes and the K_V current carried by human cloned K_V1.5 channels expressed in Ltk^– cells. Using protein kinase C (PKC)^–/– and p62^–/– mice, we demonstrate that these two proteins are involved in the K_V channel inhibition. PKC coimmunoprecipitated with K_V1.5, and this interaction was markedly reduced in p62^–/– mice. Pulmonary arteries from PKC^–/– 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. [GenBank] These data demonstrate that PKC and its adaptor protein p62 play a key role in the modulation of K_V channel function in pulmonary arteries. These observations identify PKC and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension.

Address correspondence to: Dr. Francisco Perez-Vizcaino, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. E-mail: fperez{at}med.ucm.es

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