Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I(f).
The pacemaker current I(f) of the sinoatrial node (SAN) is a major determinant of cardiac diastolic depolarization and plays a key role in controlling heart rate and its modulation by neurotransmitters. Substantial expression of 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 expression of HCN1 from rabbit SAN and its specific localization in pacemaker myocytes. rbHCN1 is an 822-amino acid protein that, in human embryonic kidney 293 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 electrophysiological properties of the channels formed by it, suggest that HCN1 plays a central and specific role in the formation of SAN pacemaker currents.
Moroni
A
A
Dipartimento di Fisiologia e Biochimica Generali, Università degli Studi di Milano, via Celoria 26, Milano 20133, Italy. anna.moroni@unimi.it
Gorza
L
L
Beltrame
M
M
Gravante
B
B
Vaccari
T
T
Bianchi
M E
ME
Altomare
C
C
Longhi
R
R
Heurteaux
C
C
Vitadello
M
M
Malgaroli
A
A
DiFrancesco
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D054815:Cyclic Nucleotide-Gated Cation Channels; D004622:Embryo, Mammalian; D006321:Heart / Q000502:physiology*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007668:Kidney; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D008969:Molecular Sequence Data; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity; D015221:Potassium Channels; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D012849:Sinoatrial Node / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D012333:RNA, Messenger; D011994:Recombinant Proteins