title: Cortactin is required for N-cadherin regulation of Kv1.5 channel function.
abstract: The intercalated disc serves as an organizing center for various cell surface components at the termini of the cardiomyocyte, thus ensuring proper mechanoelectrical coupling throughout the myocardium. The cell adhesion molecule, N-cadherin, is an essential component of the intercalated disc. Cardiac-specific deletion of N-cadherin leads to abnormal electrical conduction and sudden arrhythmic death in mice. The mechanisms linking the loss of N-cadherin in the heart and spontaneous malignant ventricular arrhythmias are poorly understood. To investigate whether ion channel remodeling contributes to arrhythmogenesis in N-cadherin conditional knock-out (N-cad CKO) mice, cardiac myocyte excitability and voltage-gated potassium channel (Kv), as well as inwardly rectifying K(+) channel remodeling, were investigated in N-cad CKO cardiomyocytes by whole cell patch clamp recordings. Action potential duration was prolonged in N-cad CKO ventricle myocytes compared with wild type. Relative to wild type, I(K,slow) density was significantly reduced consistent with decreased expression of Kv1.5 and Kv accessory protein, Kcne2, in the N-cad CKO myocytes. The decreased Kv1.5/Kcne2 expression correlated with disruption of the actin cytoskeleton and reduced cortactin at the sarcolemma. Biochemical experiments revealed that cortactin co-immunoprecipitates with Kv1.5. Finally, cortactin was required for N-cadherin-mediated enhancement of Kv1.5 channel activity in a heterologous expression system. Our results demonstrate a novel mechanistic link among the cell adhesion molecule, N-cadherin, the actin-binding scaffold protein, cortactin, and Kv channel remodeling in the heart. These data suggest that in addition to gap junction remodeling, aberrant Kv1.5 channel function contributes to the arrhythmogenic phenotype in N-cad CKO mice.
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.forename: Aaron
authors.initials: A
authors.lastname: Yung
authors.forename: Manuel
authors.initials: M
authors.lastname: Covarrubias
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C489083:Cdh2 protein, mouse; D051356:Cortactin; C489620:Kcne2 protein, mouse; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated