title: cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.
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.
  
  
  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.
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.forename: Nana
authors.initials: N
authors.lastname: Duhme
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Becker
authors.forename: Jörg
authors.initials: J
authors.lastname: Zehelein
authors.forename: Andreas
authors.initials: A
authors.lastname: Draguhn
authors.forename: Claus
authors.initials: C
authors.lastname: Bruehl
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Michael
authors.initials: M
authors.lastname: Koenen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D012849:Sinoatrial Node / Q000378:metabolism / Q000503:physiopathology; D055815:Young Adult
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D004247:DNA; D000242:Cyclic AMP