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Two pacemaker channels from human heart with profoundly different activation kinetics
Author(s) -
Ludwig Andreas,
Zong Xiangang,
Stieber Juliane,
Hullin Roger,
Hofmann Franz,
Biel Martin
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.9.2323
Subject(s) - biology , kinetics , biophysics , microbiology and biotechnology , quantum mechanics , physics
Cardiac pacemaking is produced by the slow diastolic depolarization phase of the action potential. The hyperpolarization‐activated cation current ( I f ) forms an important part of the pacemaker depolarization and consists of two kinetic components (fast and slow). Recently, three full‐length cDNAs encoding hyperpolarization‐activated and cyclic nucleotide‐gated cation channels (HCN1–3) have been cloned from mouse brain. To elucidate the molecular identity of cardiac pacemaker channels, we screened a human heart cDNA library using a highly conserved neuronal HCN channel segment and identified two cDNAs encoding HCN channels. The hHCN2 cDNA codes for a protein of 889 amino acids. The HCN2 gene is localized on human chromosome 19p13.3 and contains eight exons spanning ∼27 kb. The second cDNA, designated hHCN4 , codes for a protein of 1203 amino acids. Northern blot and PCR analyses showed that both hHCN2 and hHCN4 are expressed in heart ventricle and atrium. When expressed in HEK 293 cells, either cDNA gives rise to hyperpolarization‐activated cation currents with the hallmark features of native I f . hHCN2 and hHCN4 currents differ profoundly from each other in their activation kinetics, being fast and slow, respectively. We thus conclude that hHCN2 and hHCN4 may underlie the fast and slow component of cardiac I f , respectively.