Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development
Bernd K. Fleischmann, Yaqi Duan, Yun Fan, Torsten Schoneberg, Andreas Ehlich, Nibedita Lenka, Serge Viatchenko-Karpinski, Lutz Pott, Juergen Hescheler, Bernd Fakler
Bernd K. Fleischmann, Yaqi Duan, Yun Fan, Torsten Schoneberg, Andreas Ehlich, Nibedita Lenka, Serge Viatchenko-Karpinski, Lutz Pott, Juergen Hescheler, Bernd Fakler
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Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development

Abstract

Parasympathetic slowing of the heart rate is predominantly mediated by acetylcholine-dependent activation of the G protein–gated potassium (K+) channel (IK,ACh). This channel is composed of 2 inward-rectifier K+ (Kir) channel subunits, Kir3.1 and Kir3.4, that display distinct functional properties. Here we show that subunit composition of IK,ACh changes during embryonic development. At early stages, IK,ACh is primarily formed by Kir3.1, while in late embryonic and adult cells, Kir3.4 is the predominant subunit. This change in subunit composition results in reduced rectification of IK,ACh, allowing for marked K+ currents over the whole physiological voltage range. As a consequence, IK,ACh is able to generate the membrane hyperpolarization that underlies the strong negative chronotropy occurring in late- but not early-stage atrial cardiomyocytes upon application of muscarinic agonists. Both strong negative chronotropy and membrane hyperpolarization can be induced in early-stage cardiomyocytes by viral overexpression of the mildly rectifying Kir3.4 subunit. Thus, a switch in subunit composition is used to adopt IK,ACh to its functional role in adult cardiomyocytes.

Authors

Bernd K. Fleischmann, Yaqi Duan, Yun Fan, Torsten Schoneberg, Andreas Ehlich, Nibedita Lenka, Serge Viatchenko-Karpinski, Lutz Pott, Juergen Hescheler, Bernd Fakler

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The CCh effect is blocked by the IK,ACh -selective blocker tertiapin. (A...
The CCh effect is blocked by the IK,ACh -selective blocker tertiapin. (A) Hyperpolarization and negative chronotropy induced by CCh (1 μM) are reversed by tertiapin (1 μM) in a late-stage atrial cardiomyocyte. (B) CCh-induced deceleration of spontaneous APs is reversed by tertiapin in late-stage but not in early-stage atrial cardiomyocytes. Data are mean ± SEM of 6 early- and 7 late-stage cells (P = 0.026 for control and P = 0.0003 for CCh, unpaired Student’s t test). (C) Tertiapin-induced depolarization of the membrane potential in CCh-treated early- and late-stage atrial cardiomyocytes (P = 0.0007, unpaired Student’s t test). Recovery was estimated by determining the maximal diastolic potential prior to application of CCh and in presence of CCh and tertiapin. Asterisks denote statistically significant difference.