title: MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
abstract: A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors.
authors.affiliation: Department of Pediatrics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Abbott
authors.forename: F
authors.initials: F
authors.lastname: Sesti
authors.forename: I
authors.initials: I
authors.lastname: Splawski
authors.forename: M E
authors.initials: ME
authors.lastname: Buck
authors.forename: M H
authors.initials: MH
authors.lastname: Lehmann
authors.forename: K W
authors.initials: KW
authors.lastname: Timothy
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
authors.forename: S A
authors.initials: SA
authors.lastname: Goldstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D027682:Cation Transport Proteins; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011487:Protein Conformation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014982:Xenopus laevis
chemical_list: D027682:Cation Transport Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C059983:potassium channel protein I(sk); D011188:Potassium