title: Antiarrhythmic drug-induced internalization of the atrial-specific k+ channel kv1.5.
abstract: Conventional antiarrhythmic drugs target the ion permeability of channels, but increasing evidence suggests that functional ion channel density can also be modified pharmacologically. Kv1.5 mediates the ultrarapid potassium current (I(Kur)) that controls atrial action potential duration. Given the atrial-specific expression of Kv1.5 and its alterations in human atrial fibrillation, significant effort has been made to identify novel channel blockers. In this study, treatment of HL-1 atrial myocytes expressing Kv1.5-GFP with the class I antiarrhythmic agent quinidine resulted in a dose- and temperature-dependent internalization of Kv1.5, concomitant with channel block. This quinidine-induced channel internalization was confirmed in acutely dissociated neonatal myocytes. Channel internalization was subunit-dependent, activity-independent, stereospecific, and blocked by pharmacological disruption of the endocytic machinery. Pore block and channel internalization partially overlap in the structural requirements for drug binding. Surprisingly, quinidine-induced endocytosis was calcium-dependent and therefore unrecognized by previous biophysical studies focused on isolating channel-drug interactions. Importantly, whereas acute quinidine-induced internalization was reversible, chronic treatment led to channel degradation. Together, these data reveal a novel mechanism of antiarrhythmic drug action and highlight the possibility for new agents that selectively modulate the stability of channel protein in the membrane as an approach for treating cardiac arrhythmias.
authors.affiliation: Department of Pharmacology, 1301 MSRBIII, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0632, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Schumacher
authors.forename: Dyke P
authors.initials: DP
authors.lastname: McEwen
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Arendt
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Van Genderen
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Martens
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011802:Quinidine / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D009124:Muscle Proteins; D021122:Protein Subunits; D011802:Quinidine; D011188:Potassium