Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I-f

The pacemaker current If of the sinoatrial node (SAN) is a major determinan t of cardiac diastolic depolarization and plays a key role in controlling h eart rate and its modulation by neurotransmitters. Substantial expression o f two different mRNAs (HCN4, HCN1) of the family of pacemaker channels (HCN ) is found in rabbit SAN, suggesting that the native channels may be formed by different isoforms. Here we report the cloning and heterologous express ion of HCN1 from rabbit SAN and its specific localization in pacemaker myoc ytes. rbHCN1 is an 822-amino acid protein that, in human embryonic kidney 2 93 cells, displayed electrophysiological properties similar to those of I-f suggesting that HCN1 can form a pacemaker channel. The presence of HCN1 in the SAN myocytes but not in nearby heart regions, and the electrophysiolog ical properties of the channels formed by it, suggest that HCN1 plays a cen tral and specific role in the formation of SAN pacemaker currents.