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Sinoatrial node
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HCN4
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Atrial fibrillation
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Tachyarrhythmia
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Ion channels
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Pacemake
Abstract:
HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is
associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to
the generation of cardiac tachyarrhythmias.
Methods
and results
In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected
a novel
HCN4
gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4-K530N) in a
highly conserved region of the C-linker. The index patient developed tachycardia – bradycardia syndrome and persist-
ent atrial fibrillation (AF) in an age-dependent fashion. Pedigree analysis identified eight affected family members with
a similar course of disease. Whole-cell patch clamp electrophysiology of HEK293 cells showed that homomeric
mutant channels almost are indistinguishable from wild-type channels. In contrast, heteromeric channels composed
of mutant and wild-type subunits displayed a significant hyperpolarizing shift in the half-maximal activation voltage.
This may be caused by a shift in the equilibrium between the tonically inhibited nucleotide-free state of the
C-terminal domain of HCN4 believed to consist of a ‘dimer of dimers’ and the activated ligand-bound tetrameric
form, leading to an increased inhibition of activity in heteromeric channels.
Conclusion
Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia – bradycardia
syndrome and persistent AF, indicating that f-channel dysfunction contributes to the development of atrial
tachyarrhythmia
