Heteromultimeric assembly of human potassium channels. Molecular basis of a transient outward current?
To gain insight into the molecular basis of cardiac repolarization, we have expressed K+ channels cloned from ventricular myocardium in Xenopus oocytes. A recently identified human cardiac K+ channel isoform (human Kv1.4) has properties similar to the 4-aminopyridine-sensitive calcium-insensitive component of the cardiac transient outward current. However, these channels recovered from inactivation much slower than native channels. Hybrid channels consisting of subunits from different K+ channel clones (delayed rectifier channels [Kv1.1, Kv1.2, and Kv1.5] and Kv1.4) were created by coinjection of cRNAs in oocytes. Multimeric channels consisting of Kv1.4:Kv1.1, Kv1.4:Kv1.2, and Kv1.4:Kv1.5 were expressed and compared. The hybrid channels displayed characteristics of heterotetrameric channels with kinetics that more closely resembled a native cardiac transient outward current. The inactivation and recovery from inactivation of the heteromeric channels indicated that the presence of a single inactivating subunit (Kv1.4) was probably sufficient to cause channel inactivation. The results demonstrate that expression of different K+ channel genes can produce channel protein subunits that assemble as heteromultimers with unique properties. It is shown that certain combinations of voltage-gated K+ channels probably do not contribute to native transient outward current. However, one combination of subunits could not be excluded. Therefore, this mechanism of channel assembly may underlie some of the functional diversity of potassium channels found in the cardiovascular system.
Department of Pharmacology, Vanderbilt University Medical School, Nashville, Tenn. 37232-2171.
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Roberds
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Snyders
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Tamkun
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Bennett
D000818:Animals; D003001:Cloning, Molecular; D003198:Computer Simulation; D005260:Female; D006801:Humans; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008956:Models, Chemical; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014981:Xenopus
D046911:Macromolecular Substances; D015221:Potassium Channels; D011994:Recombinant Proteins; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium