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          Institute: MPI für medizinische Forschung     Collection: Abteilung Molekulare Neurobiologie     Display Documents

ID: 545957.0, MPI für medizinische Forschung / Abteilung Molekulare Neurobiologie
cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control
Translation of Title:cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control
Authors:Schweizer, P. A.; Duhme, N.; Thomas, D.; Becker, Roland; Zehelein, Joerg; Draguhn, Andreas; Bruehl, C.; Katus, H. A.; Koenen, Mascha
Date of Publication (YYYY-MM-DD):2010-08-07
Title of Journal:Circulation: Arrhythmia & Electrophysiology
Journal Abbrev.:Circulation: Arrhythmia & Electrophysiology
Issue / Number:5
Start Page:542
End Page:552
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Background: HCN channels activate the pacemaker current If, 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 female 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 composed of
wildtype 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 seven additional living carriers showing similar clinical
phenotypes, i.e. sinus node dysfunction with mean resting heart rate of 45.9 ± 4.6 bpm (n=8)
compared to 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, mutantcarriers
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 If determines basal heart rate but is not
critical for maximum heart rate, heart rate variability or chronotropic competence.
Furthermore, cAMP−activated If may stabilize heart rhythm during chronotropic response.
Free Keywords:Sinoatrial node, pacemaker, heart rate, ion channels, electrophysiology, HCN
Last Change of the Resource (YYYY-MM-DD):--
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Abteilung Zellphysiologie
MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie
MPI für medizinische Forschung/Arbeitsgruppe Witzemann / Koenen
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