title: Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.
abstract: KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K(+) current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4-5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential.
authors.affiliation: Center for Muscle Biology, Department of Physiology, University of Kentucky, Lexington, Kentucky;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Smith
authors.forename: Allison R
authors.initials: AR
authors.lastname: Reloj
authors.forename: Parvathi S
authors.initials: PS
authors.lastname: Nataraj
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bartos
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroder
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Corey L
authors.initials: CL
authors.lastname: Anderson
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; C063968:E 4031
keywords: long QT syndrome; potassium channel; trafficking