RT Journal Article
SR Electronic
T1 Role of Protein Kinase Cζ and Its Adaptor Protein p62 in Voltage-Gated Potassium Channel Modulation in Pulmonary Arteries
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1301
OP 1309
DO 10.1124/mol.107.037002
VO 72
IS 5
A1 Laura Moreno
A1 Giovanna Frazziano
A1 Angel Cogolludo
A1 Laura Cobeño
A1 Juan Tamargo
A1 Francisco Perez-Vizcaino
YR 2007
UL http://molpharm.aspetjournals.org/content/72/5/1301.abstract
AB Voltage-gated potassium (KV) 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 KV channels. In the current study, we aimed to elucidate the role of PKCζ and its adaptor protein p62 in the modulation of KV channels. We report that the thromboxane A2 analog 9,11-dideoxy-11α,9α-epoxymethano-prostaglandin F2α methyl acetate (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 protein kinase C (PKC)ζ–/– and p62–/– mice, we demonstrate that these two proteins are involved in the KV channel inhibition. PKCζ coimmunoprecipitated with KV1.5, and this interaction was markedly reduced in p62–/– mice. Pulmonary arteries from PKCζ–/– 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 PKCζ and its adaptor protein p62 play a key role in the modulation of KV channel function in pulmonary arteries. These observations identify PKCζ and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension. The American Society for Pharmacology and Experimental Therapeutics