The cardiac pacemaker current.
In mammals cardiac rate is determined by the duration of the diastolic depolarization of sinoatrial node (SAN) cells which is mainly determined by the pacemaker I(f) current. f-channels are encoded by four members of the hyperpolarization-activated cyclic nucleotide-gated gene (HCN1-4) family. HCN4 is the most abundant isoform in the SAN, and its relevance to pacemaking has been further supported by the discovery of four loss-of-function mutations in patients with mild or severe forms of cardiac rate disturbances. Due to its selective contribution to pacemaking, the I(f) current is also the pharmacological target of a selective heart rate-reducing agent (ivabradine) currently used in the clinical practice. Albeit to a minor extent, the I(f) current is also present in other spontaneously active myocytes of the cardiac conduction system (atrioventricular node and Purkinje fibres). In working atrial and ventricular myocytes f-channels are expressed at a very low level and do not play any physiological role; however in certain pathological conditions over-expression of HCN proteins may represent an arrhythmogenic mechanism. In this review some of the most recent findings on f/HCN channels contribution to pacemaking are described.
Baruscotti
Mirko
M
Department of Biomolecular Sciences and Biotechnology, Laboratory of Molecular Physiology and Neurobiology, Università degli Studi di Milano, Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), via Celoria 26, 20133 Milano, Italy. mirko.baruscotti@unimi.it
Barbuti
Andrea
A
Bucchi
Annalisa
A
D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism
D054815:Cyclic Nucleotide-Gated Cation Channels