Control of heart rate by cAMP sensitivity of HCN channels
- 21 July 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 106 (29), 12189-12194
- https://doi.org/10.1073/pnas.0810332106
Abstract
"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.Keywords
This publication has 32 references indexed in Scilit:
- Calmodulin kinase II is required for fight or flight sinoatrial node physiologyProceedings of the National Academy of Sciences, 2009
- Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMPThe EMBO Journal, 2008
- HCN4 provides a ‘depolarization reserve’ and is not required for heart rate acceleration in miceThe EMBO Journal, 2007
- Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker functionCardiovascular Research, 2007
- Chronic heart rate reduction remodels ion channel transcripts in the mouse sinoatrial node but not in the ventriclePhysiological Genomics, 2006
- Serious workings of the funny currentProgress in Biophysics and Molecular Biology, 2006
- Heart Rate Lowering by Specific and Selective If Current Inhibition with IvabradineDrugs, 2004
- Facilitation of the L-type calcium current in rabbit sino-atrial cells: effect on cardiac automaticityCardiovascular Research, 2000
- The Mode Selection Trial (MOST) in sinus node dysfunction: Design, rationale, and baseline characteristics of the first 1000 patientsAmerican Heart Journal, 2000
- Influence of heart rate on mortality among persons with hypertension: The Framingham StudyAmerican Heart Journal, 1993