Funny channels in the control of cardiac rhythm and mode of action of selective blockers.
"Funny" (f) channels underlie the cardiac "pacemaker"I(f) current, originally described as an inward current activated on hyperpolarization to the diastolic range of voltages in sino-atrial node myocytes [Brown, HF, DiFrancesco, D, Noble, SJ. How does adrenaline accelerate the heart? Nature 1979;280:235-236]. The involvement of funny channels in the generation and modulation of cardiac pacemaker activity has been amply demonstrated by thorough analysis since its discovery. The degree of funny current activation upon termination of an action potential determines the slope of diastolic depolarization, and hence pacemaker frequency; furthermore, I(f) is under cAMP-mediated control by beta-adrenergic and muscarinic stimulation and underlies the modulation of cardiac rate by the autonomous nervous system: it therefore represents a mechanism of fundamental physiological relevance. Their function in pacemaking makes funny channels an obvious target for drugs aiming at regulation of spontaneous activity and cardiac rate. This explains the recent development of "heart rate-reducing" drugs which act as selective f-channel inhibitors, and as such are capable of specifically slow cardiac frequency by decreasing the rate of diastolic depolarization. These substances will be useful in treating diseases such as chronic angina and heart failure. Furthermore, in situ delivery of funny channels, or of a cellular source of funny channels, is a promising new technique for the development of biological pacemakers which may in a near future replace electronic devices. Finally, a channel mutation responsible for one type of a relatively common rhythm disturbance, sinus bradycardia, has been recently identified, highlighting the clinical relevance of funny channels in the pacemaker function.
DiFrancesco
Dario
D
University of Milano, Department of Biomolecular Sciences and Biotechnology, Laboratory of Molecular Physiology and Neurobiology, via Celoria 26, 20133 Milano, Italy. dario.difrancesco@unimi.it
D000818:Animals; D001341:Autonomic Nervous System; D001552:Benzazepines / Q000494:pharmacology; D001919:Bradycardia / Q000235:genetics / Q000628:therapy; D017690:Cell Transplantation; D054815:Cyclic Nucleotide-Gated Cation Channels; D003864:Depression, Chemical; D003971:Diastole; D015316:Genetic Therapy; D006321:Heart / Q000294:innervation / Q000502:physiology*; D006327:Heart Block / Q000628:therapy; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D000077550:Ivabradine; D009124:Muscle Proteins / Q000235:genetics; D017354:Point Mutation; D015221:Potassium Channels
D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine