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Ventricular pacemaker current (I(f)) shows distinct voltage dependence as a function of age, activating outside the physiological range in normal adult ventricle, but less negatively in neonatal ventricle. However, heterologously expressed HCN2 and HCN4, the putative molecular correlates of ventricular I(f), exhibit only a modest difference in activation(More)
Cardiac pacemaking generation and modulation rely on the coordinated activity of several processes. Although a wealth of evidence indicates a relevant role of the I(f) ("funny," or pacemaker) current, whose molecular constituents are the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and particularly HCN4, work with mice where Hcn genes(More)
Human cDNA coding for the hyperpolarization-activated "pacemaker" channel HCN2 was expressed in Phoenix cells and yielded an inward current (IhHCN2) activated on hyperpolarization. The average IhHCN2 was half-activated at -83.1 mV and its kinetics could be described by second-order Hodgkin-Huxley gating. The time constant curve was bell-shaped and peaked at(More)
BACKGROUND Establishment of a biological pacemaker is expected to solve the persisting problems of a mechanical pacemaker including the problems of battery life and electromagnetic interference. Enhancement of the funny current (If) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and attenuation of the inward rectifier K+(More)
Activation of the pacemaker ("funny," I(f)) current during diastole is the main process underlying generation of the diastolic depolarization and spontaneous activity of cardiac pacemaker cells. I(f) modulation by autonomic transmitters is responsible for the chronotropic regulation of heart rate. Given its role in pacemaking, I(f) has been a major target(More)
beta(1)- and beta(2)-adrenergic receptors (ARs) coexist in different regions of the heart. The beta(2)/beta(1) expression ratio is higher in the sinoatrial node (SAN) than in atria and ventricles, but the specific contribution of either type of receptor to rate modulation is still not well established. We have recently demonstrated that pacemaker ("funny")(More)
Activation of the "funny" (pacemaker, I f) current during the diastolic depolarization phase of an action potential is the main mechanism underlying spontaneous, rhythmic activity of cardiac pacemaker cells. In the past three decades, a wealth of evidence elucidating the function of the funny current in the generation and modulation of cardiac pacemaker(More)
Lipid rafts are discrete membrane subdomains rich in sphingolipids and cholesterol. In ventricular myocytes a function of caveolae, a type of lipid rafts, is to concentrate in close proximity several proteins of the beta-adrenergic transduction pathway. We have investigated the subcellular localization of HCN4 channels expressed in HEK cells and studied the(More)
Pacemaker channels are encoded by the HCN gene family and are responsible for a variety of cellular functions including control of spontaneous activity in cardiac myocytes and control of excitability in different types of neurons. Some of these functions require specific membrane localization. Although several voltage-gated channels are known to interact(More)
In the adult animal the sinoatrial node (SAN) rhythmically generates a depolarizing wave that propagates to the rest of the heart. However, the SAN is more than a simple clock; it is a clock that adjusts its pace according to the metabolic requirements of the organism. The Hyperpolarization-activated Cyclic Nucleotide-gated channels (HCN1-4) are the(More)