Control of heart rate by cAMP sensitivity of HCN channels.
"Pacemaker" f-channels mediating the hyperpolarization-activated nonselective cation current I(f) are directly regulated by cAMP. Accordingly, the activity of f-channels increases when cellular cAMP levels are elevated (e.g., during sympathetic stimulation) and decreases when they are reduced (e.g., during vagal stimulation). Although these biophysical properties seem to make f-channels ideal molecular targets for heart rate regulation by the autonomic nervous system, the exact contribution of the major I(f)-mediating cardiac isoforms HCN2 and HCN4 to sinoatrial node (SAN) function remains highly controversial. To directly investigate the role of cAMP-dependent regulation of hyperpolarization activated cyclic nucleotide activated (HCN) channels in SAN activity, we generated mice with heart-specific and inducible expression of a human HCN4 mutation (573X) that abolishes the cAMP-dependent regulation of HCN channels. We found that hHCN4-573X expression causes elimination of the cAMP sensitivity of I(f) and decreases the maximum firing rates of SAN pacemaker cells. In conscious mice, hHCN4-573X expression leads to a marked reduction in heart rate at rest and during exercise. Despite the complete loss of cAMP sensitivity of I(f), the relative extent of SAN cell frequency and heart rate regulation are preserved. Our data demonstrate that cAMP-mediated regulation of I(f) determines basal and maximal heart rates but does not play an indispensable role in heart rate adaptation during physical activity. Our data also reveal the pathophysiologic mechanism of hHCN4-573X-linked SAN dysfunction in humans.
Alig
Jacqueline
J
Experimental Neuropediatrics, Center for Obstetrics and Pediatrics & Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Marger
Laurine
L
Mesirca
Pietro
P
Ehmke
Heimo
H
Mangoni
Matteo E
ME
Isbrandt
Dirk
D
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000187:drug effects; D000077550:Ivabradine; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D010805:Physical Conditioning, Animal; D015221:Potassium Channels; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D050505:Mutant Proteins; D015221:Potassium Channels; D000077550:Ivabradine; D000242:Cyclic AMP