PubMed 26655221

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Title: Molecular Determinants of Kv1.3 Potassium Channels-Induced Proliferation.

Authors: Laura Jiménez-Pérez, Pilar Cidad, Inés Álvarez-Miguel, Alba Santos-Hipólito, Rebeca Torres-Merino, Esperanza Alonso, Miguel Ángel de la Fuente, José Ramón López-López, M Teresa Pérez-García

Journal, date & volume: J. Biol. Chem., 2015 Dec 10 , ,

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Changes in voltage-dependent potassium channels (Kv channels) associate to proliferation in many cell types, including transfected HEK293 cells. In this system, Kv1.5 overexpression decreases proliferation while Kv1.3 expression increases it independently of K+ fluxes. To identify Kv1.3 domains involved in proliferation-associated signaling mechanism(s), we constructed chimeric Kv1.3-Kv1.5 channels and point-mutant Kv1.3 channels, which were expressed as GFP- or cherry-fusion proteins. We studied their trafficking and functional expression, combining immunocytochemical and electrophysiological methods, and their impact on cell proliferation. We found that the C-terminus is necessary for Kv1.3-induced proliferation. We distinguished two residues (Y447 and S459) whose mutation to alanine abolished proliferation. The insertion into Kv1.5 of a sequence comprising these two residues increased proliferation rate. Moreover, Kv1.3 voltage-dependent transitions from closed to open conformation induced MEK-ERK1/2-dependent Y447 phosphorylation. We conclude that the mechanisms for Kv1.3-induced proliferation involve the accessibility of key docking sites at the C-terminus. For one of these sites (Y447) we demonstrated the contribution of MEK/ERK dependent phosphorylation, which is regulated by voltage-induced conformational changes.