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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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 1

Popdc2–/– mice develop a stress-induced bradycardia.

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Popdc2–/– mice develop a stress-induced bradycardia. (A) Consecutiv...
(A) Consecutive sections of a Popdc2+/– mouse heart were stained for β-galactosidase (LacZ) and acetylcholine esterase (AChE). (B) A section through the vena cava region was LacZ stained for 10 or 80 minutes. (C) Whole-mount LacZ staining and (D) in situ hybridization for Popdc2. Arrowheads and arrows in A, C, and D denote sinus and AV nodes, respectively. RA, right atrium; SAN, sinus node. Scale bars: 1 mm (A); 200 μm (B); 500 μm (C and D). (E) Heart rate distribution (y axis) of 8-month-old Popdc2–/– and WT mice before (green), during (blue), and after (red) swim stress, depicted on a beat per beat basis (x axis). (F) Age-dependent mean heart rates of WT and Popdc2–/– mice during and after swimming. *P < 0.05 between genotypes (n = 5–12). (G) ECG recordings of 8-month-old Popdc2–/– and WT mice during swim stress test. Asterisks indicate P waves. Horizontal bar: 100 ms. (H) Number of pauses in WT and Popdc2–/– mice during a 30-minute period after swim stress (log scale on y axis) as a function of age (x axis). *P < 0.05 between genotypes (n = 5–12). (I) PQ intervals measured at 600, 450, and 150 bpm (n = 5 per genotype and heart rate). ne, nonexistent in WT. (J) Number of isolated hearts with sinus pauses after β-adrenergic stimulation. *P < 0.05 between genotypes; #P < 0.05, baseline vs. catecholamine.