Differential subunit composition of the G protein–activated inward-rectifier potassium channel during cardiac development
Bernd K. Fleischmann, … , Juergen Hescheler, Bernd Fakler
Bernd K. Fleischmann, … , Juergen Hescheler, Bernd Fakler
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):994-1001. https://doi.org/10.1172/JCI15925.
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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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Figure 1

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Chronotropy differs between early- and late-stage atrial cardiomyocytes....
Chronotropy differs between early- and late-stage atrial cardiomyocytes. (A) Spontaneous APs are distinctly slowed by CCh (1 μM) in early- (left panel) and late-stage (right panel) cardiomyocytes. APs were recorded under current-clamp conditions; CCh was bath applied. (B) Percentage of cells displaying chronotropic effect and membrane hyperpolarization following application of CCh. Note that only 60% of early-stage cells display hyperpolarization upon application of CCh. (C) AP frequency of early- and late-stage cardiomyocytes before and after application of CCh; data are mean ± SEM of 8 and 9 experiments (P = 0.016 for control and P = 0.022 for CCh, unpaired Student’s t test). (D) Hyperpolarization induced by CCh in early and late stage cardiomyocytes; data are mean ± SEM of 6 and 9 experiments, respectively (P = 0.002, unpaired Student’s t test). Asterisks denote statistically significant difference.