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  cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control

Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., et al. (2010). cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control. Circulation: Arrhythmia and Electrophysiology, 3(5), 542-552. doi:10.1161/CIRCEP.110.949768.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-5DAB-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-5DAC-A
Genre: Journal Article
Alternative Title : cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control

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CirculArrhythmElectrophysiol_3_2010_542.pdf (Any fulltext), 845KB
 
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 Creators:
Schweizer, Patrick A., Author
Duhme, Nana, Author
Thomas, Dierck, Author
Becker, Rüdiger, Author
Zehelein, Joerg1, Author              
Draguhn, Andreas2, Author              
Bruehl, Claus, Author
Katus, Hugo A., Author
Koenen, Michael1, Author              
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              

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Free keywords: Sinoatrial node, pacemaker, heart rate, ion channels, electrophysiology, HCN channels
 Abstract: BACKGROUND: HCN channels activate the pacemaker current I(f), which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation. METHODS AND RESULTS: In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia. Biophysical properties determined by whole-cell patch-clamp recording of HEK293 cells demonstrated that mutant subunits (HCN4-695X) were insensitive to cAMP. Heteromeric channels composed of wild-type and mutant subunits failed to respond to cAMP-like homomeric mutant channels, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Pedigree analysis identified 7 additional living carriers showing similar clinical phenotypes, that is, sinus node dysfunction with mean resting heart rate of 45.9±4.6 bpm (n=8) compared with 66.5±9.1 bpm of unaffected relatives (n=6; P<0.01). Clinical evaluation revealed no ischemic or structural heart disease in any family member. Importantly, mutant carriers exhibited normal heart rate variance and full ability to accelerate heart rate under physical activity or pharmacological stimulation. Moreover, mutant carriers displayed distinctive sinus arrhythmias and premature beats linked to adrenergic stress. CONCLUSIONS: In humans, cAMP responsiveness of I(f) determines basal heart rate but is not critical for maximum heart rate, heart rate variability, or chronotropic competence. Furthermore, cAMP-activated I(f) may stabilize heart rhythm during chronotropic response.

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Language(s): eng - English
 Dates: 2010-03-012010-07-152010-08-072010-10-20
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 664570
DOI: 10.1161/CIRCEP.110.949768
URI: http://www.ncbi.nlm.nih.gov/pubmed/20693575
Other: 7600
 Degree: -

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Title: Circulation: Arrhythmia and Electrophysiology
  Alternative Title : Circulation: Arrhythmia and Electrophysiology
Source Genre: Journal
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Publ. Info: Philadelphia, Pa. : Lippincott, Williams & Wilkins
Pages: - Volume / Issue: 3 (5) Sequence Number: - Start / End Page: 542 - 552 Identifier: ISSN: 1941-3149