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. 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 45.9Ϯ4.6 bpm (nϭ8) compared with 66.5Ϯ9.1 bpm of unaffected relatives (nϭ6; PϽ0.01). 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. (Circ Arrhythm Electrophysiol. 2010;3:542-552.)

Free energy landscape remodeling of the cardiac pacemaker channel explains the molecular basis of familial sinus bradycardia

“…Together the C-helix and the CTL define the CBD lid (Fig. 1B), which is indispensable for cAMP signaling via HCN channels (9,11). Deletion of the lid, even partially, is sufficient to render HCN channel gating insensitive to cAMP (9,11).…”

“…Mutations that perturb or disrupt this coupling cause pathological conditions for the heart and pacemaker current (11,(15)(16)(17)(18)(19). For example, alteration of the highly conserved Ser-672 residue in the HCN4 CBD by the heterozygous S672R mutation results in bradycardia, i.e.…”

Mechanism of Sinus Bradycardia in Carriers of the 1795insD Mutation in the SCN5A Gene

“…Together, the loss-offunction effects of the shifts in the voltage dependence of 1795insD 41 ± 1** 70 ± 1** 124 ± 3** 54 47 ± 1 77 ± 2 141 ± 3 40 Van den Berg et al [12] In HCN4 G480R 32 ± 8* 49 ± 12* 101 ± 21* 7 55 ± 9 73 ± 11 126 ± 17 8 Nof et al [13] A485V 37 ± 3* 58 ± 6* 117 ± 27 14 49 ± 11 77 ± 12 140 ± 33 5 Laish-Farkash et al [14] 695X 36 ± 6* 56 ± 5* 131 ± 17 7 47 ± 6 72 ± 10 157 ± 26 6 Schweizer et al [15] Minimum (Min), average (Avg), and maximum (Max) heart rate (HR) obtained with 24-hour Holter recording. Data are mean ± SEM.…”

“…Holter recording in 1795insD patients revealed sinus bradycardia with an ≈11% decrease in minimum, average, and maximum heart rate [12], as detailed in Table 1, which also shows the bradycardic effect of some typical HCN4 mutations [13][14][15] for comparison.…”

Bradycardic Effects of Mutations in the HCN4 Gene at Different Levels of Autonomic Tone in Humans

“…The average heart rate of 14 mutation carriers was 58 ± 6 bpm (range 49-70 bpm), whereas that of 5 non-carriers was 77 ± 12 bpm (range 59-91 bpm). In a single German family with the 695X mutation, Schweizer et al [11] observed an average heart rate of 56 ± 5 bpm (range 47-61 bpm) in 7 mutation carriers vs. 72 ± 10 bpm (range 58-86 bpm) in 6 non-carriers. The clinical data of Nof et al [9], Laish-Farkash et al [10], and Schweizer et al [11] are not limited to the average heart rate.…”