Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice
Alexander Froese, … , Larissa Fabritz, Thomas Brand
Alexander Froese, … , Larissa Fabritz, Thomas Brand
Published February 22, 2012
Citation Information: J Clin Invest. 2012;122(3):1119-1130. https://doi.org/10.1172/JCI59410.
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Research Article

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Abstract

Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.

Authors

Alexander Froese, Stephanie S. Breher, Christoph Waldeyer, Roland F.R. Schindler, Viacheslav O. Nikolaev, Susanne Rinné, Erhard Wischmeyer, Jan Schlueter, Jan Becher, Subreena Simrick, Franz Vauti, Juliane Kuhtz, Patrick Meister, Sonja Kreissl, Angela Torlopp, Sonja K. Liebig, Sandra Laakmann, Thomas D. Müller, Joachim Neumann, Juliane Stieber, Andreas Ludwig, Sebastian K. Maier, Niels Decher, Hans-Henning Arnold, Paulus Kirchhof, Larissa Fabritz, Thomas Brand

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Figure 3

Structural alterations of the sinus node in Popdc2–/– mice.

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Structural alterations of the sinus node in Popdc2–/– mice. (A–D) Wh...
(A–D) Whole-mount immunohistochemistry of HCN4 expression in the sinus node. Boxed regions in A and B are enlarged in C and D, respectively. Arrowheads in C and D denote the network of filopodia-like extensions of nodal myocytes that were structurally abnormal in Popdc2–/– mice. (E and F) Whole-mount immunofluorescence staining of HCN4 in the sinus node illustrating an overall reduction of pacemaking cells in Popdc2–/– mice. (G and H) 3D reconstruction of the sinus node based on HCN4 expression. Arrowheads in E–H indicate reduction of HCN4 immunoreactivity in the inferior part of the sinus node in mutant mice. Bars at right denote approximate planes of sections shown in I–P. (I–L) Trichrome staining visualizing the histology and fibrotic tissue content in the superior (I and J) and inferior (K and L) region of the sinus node. (M–P) Immunohistochemistry for HCN4 expression in the superior (M and N) and inferior (O and P) part of the sinus node. Scale bars: 200 μm (A and B); 100 μm (C–P).