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. 2008 Oct 7;105(40):15617-22.
doi: 10.1073/pnas.0805500105. Epub 2008 Oct 1.

Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease

Solena Le Scouarnec  1 , Naina Bhasin, Claude Vieyres, Thomas J Hund, Shane R Cunha, Olha Koval, Celine Marionneau, Biyi Chen, Yuejin Wu, Sophie Demolombe, Long-Sheng Song, Hervé Le Marec, Vincent Probst, Jean-Jacques Schott, Mark E Anderson, Peter J Mohler
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V体育2025版 - Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease

Solena Le Scouarnec (VSports在线直播) et al. Proc Natl Acad Sci U S A. .

"VSports" Abstract

The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing VSports手机版. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
SND in human kindreds with ANK2 allele variants. (A) Family 1: Affected patients carry an AnkB-E1425G mutation depicted by a plus, whereas noncarriers are depicted by a minus. Other individuals did not undergo genetic testing. Note that at least 23 of 25 variant carriers (92%) display SND. (B) Family 2: Affected patients carry a common haplotype depicted by a black bar at the ANK2 locus. Markers D4S1572 and D4S427 delimitate the disease haplotype to a 16.5 cM interval (recombinations for patients III-9 and II-1, respectively). Squares represent males and circles represent females.
Fig. 2.
Fig. 2.
Ankyrin-B is expressed in human and mouse SAN and AnkB+/− mice display severe SND. (A) Adult AnkB− mice exhibit significant bradycardia and heart rate variability. Data represents mean ± SD for eight mice/genotype. (B) Immunoblots of human SAN tissue for SAN resident proteins HCN4, Cav3.1, Cav1.3, NCX1, and Cx45. Note that Cx43 is not a SAN-resident protein. We observed decreased expression of AnkB in all SAN preparations. (C) AnkB is expressed in SAN of the WT mouse heart and is significantly reduced in AnkB+/− adult mice. Equal protein loading was assessed by blotting for unrelated protein (data not shown, NHERF1). (D and E) AnkB is expressed in the mouse SAN. WT and AnkB+/− mouse sections were immunolabeled for AnkB and SAN markers HCN4 and neurofilament, and imaged by using identical protocols. E indicates loss of AnkB expression in AnkB+/− mice. (Scale bars, 10 μm.) (F and G) Expression of AnkB in isolated WT and AnkB+/− SAN cells. (Scale bars, 10 μm.)
Fig. 3.
Fig. 3.
NCX1, IP3R, Na/K ATPase, and Cav1.3 membrane expression is affected in AnkB+/− SAN cells. (A–P) Confocal imaging of SAN cells from WT and AnkB+/− mice. SAN cells were immunolabeled and imaged by using identical protocols. Note that NCX1 (A and B), Na/K ATPase (NKA) (M and N), and IP3R (O and P) immunolabeling is generally reduced across the cell, whereas Cav1.3 immunostaining is concentrated near the perinuclear region of AnkB+/− SAN cells (E and F). WT and AnkB+/− SAN cells displayed no difference in the expression or localization of Cav1.2 (C and D), Cav3.1 (G and H), HCN4 (I and J), RyR2 (K and L), or connexin 40 (data not shown). (Scale bars, 10 μm.)
Fig. 4.
Fig. 4.
Reduced INCX and ICa,L in AnkB+/− SAN cells. Reduction of AnkB leads to reduced NCX1 and L-type Ca2+ currents. (A) INCX density is significantly lower in isolated AnkB+/− SAN cells compared to WT at voltages greater than 0 mV (n = 12, P < 0.05). Raw trace and bar graph represent current at −10 mV. (B) ICa density is reduced significantly in isolated AnkB+/− SAN cells compared to WT cells at all voltages tested (n = 10, P < 0.05). Raw trace and bar graph represent current at −10 mV. (C and D) T-type Ca2+ current is unchanged between WT and AnkB+/− SAN cells (n = 10, NS), whereas L-type Ca2+ current is dramatically reduced in AnkB+/− SAN cells (n = 10, P < 0.05). Raw traces and bar graphs represent current at −20 mV (ICa,T) and 0 mV (ICa,L). (E) WT and AnkB+/− SAN cells display similar If current (n = 10, NS). Bar graph represents current at −80 mV.
Fig. 5.
Fig. 5.
AnkB is required for SAN Ca2+ homeostasis. (A) Rate and frequency of Ca2+ transients from isolated SAN cells of WT and AnkB+/− mice were measured by using Fluo-3 AM and confocal imaging. Note reduced rate and extreme rate variability in AnkB+/− SAN cells. (B) Fourier transformation of pooled data from eight independent experiments from rate and frequency measurements in A. Note that AnkB+/− SAN explants display increased power density at ≥2 dominant frequencies. (C) Ca2+ transients of WT and AnkB+/− mouse SAN. AnkB+/− cells display increased cycle length and inconsistent response to isoproterenol. (D) Mean data from isoproterenol experiments. (n = 8 per genotype, P < 0.05.)
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References (VSports最新版本)

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