title: Molecular basis and drug sensitivity of the delayed rectifier (IKr) in the fish heart.
abstract: Fishes are increasingly used as models for human cardiac diseases, creating a need for a better understanding of the molecular basis of fish cardiac ion currents. To this end we cloned KCNH6 channel of the crucian carp (Carassius carassius) that produces the rapid component of the delayed rectifier K(+) current (IKr), the main repolarising current of the fish heart. KCNH6 (ccErg2) was the main isoform of the Kv11 potassium channel family with relative transcript levels of 98.9% and 99.6% in crucian carp atrium and ventricle, respectively. KCNH2 (ccErg1), an orthologue to human cardiac Erg (Herg) channel, was only slightly expressed in the crucian carp heart. The native atrial IKr and the cloned ccErg2 were inhibited by similar concentrations of verapamil, terfenadine and KB-R7943 (P>0.05), while the atrial IKr was about an order of magnitude more sensitive to E-4031 than ccErg2 (P<0.05) suggesting that some accessory β-subunits may be involved. Sensitivity of the crucian carp atrial IKr to E-4031, terfenadine and KB-R7943 was similar to what has been reported for the Herg channel. In contrast, the sensitivity of the crucian carp IKr to verapamil was approximately 30 times higher than the previously reported values for the Herg current. In conclusion, the cardiac IKr is produced by non-orthologous gene products in fish (Erg2) and mammalian hearts (Erg1) and some marked differences exist in drug sensitivity between fish and mammalian Erg1/2 which need to be taken into account when using fish heart as a model for human heart.
authors.affiliation: University of Eastern Finland, Department of Biology, P.O. Box 111, 80101 Joensuu, Finland. Electronic address: Minna.Hassinen@uef.fi.
authors.forename: Minna
authors.initials: M
authors.lastname: Hassinen
authors.affiliation: University of Eastern Finland, Department of Biology, P.O. Box 111, 80101 Joensuu, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Haverinen
authors.affiliation: University of Eastern Finland, Department of Biology, P.O. Box 111, 80101 Joensuu, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Vornanen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002347:Carps / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D003412:Cricetulus; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D029941:Fish Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials; D023421:Models, Animal; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity; D014162:Transfection
chemical_list: D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D029941:Fish Proteins; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D011188:Potassium
keywords: Cardioactive drugs; Delayed rectifier potassium current; Erg channels; Fish heart