Functional coupling of human beta 3-adrenoreceptors to the KvLQT1/MinK potassium channel.
The slow component of the delayed rectifier potassium current (IKs) plays an important role during repolarization in the human heart. Life-threatening arrhythmias can be triggered by sympathetic stimulation, presumably acting on IKs. The ion channel responsible for the IKs current is made of two proteins, the KvLQT1 protein and the MinK protein. In this study, we investigated the effects of adrenergic stimulation on the KvLQT1/MinK channel by coexpressing KvLQT1/MinK channels with the human beta(3)-adrenoreceptor subunit heterologously in Xenopus oocytes. Western blot experiments revealed that beta(3)-adrenoreceptor proteins appear in the cell membrane of Xenopus oocytes, when the corresponding cRNA was injected. In electrophysiological measurements we found that stimulation with the beta-adrenergic agonist isoproterenol increased the current amplitude of the beta(3)/KvLQT1/MinK complex up to 237% with an ED(50) of 8 nm, a value similar to that found on IKs in guinea pig cardiomyocytes. When oocytes with beta(3)/KvLQT1/MinK were preincubated with cholera toxin (2 microg/ml), an activator of G(S) proteins, the basal current amplitude of the beta(3)/KvLQT1/MinK complex was increased 3.1-fold, and the current amplitude increase by isoproterenol was drastically reduced, indicating that the signal transduction cascade was mediated via G(s) proteins. The knowledge about functional coupling of the human beta(3)-adrenoreceptor to KvLQT1/MinK channels reveals interesting aspects about the genesis and therapy of arrhythmias.
Kathöfer
S
S
Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, D-69115 Heidelberg, Germany.
Zhang
W
W
Karle
C
C
Thomas
D
D
Schoels
W
W
Kiehn
J
J
D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3; D014982:Xenopus laevis
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D019204:GTP-Binding Proteins