Funny current

Funny current (or I_f, or I_Kf, or pacemaker current) is an electric current in the heart that flows through the funny channel (which comprises the HCN channels, that is, pacemaker channels). Such channels are important parts of the electrical conduction system of the heart and help constitute the natural pacemaker.

First described in the late 1970s in Purkinje fibers and sinoatrial myocytes, the cardiac pacemaker "funny" (I_f) current has been extensively characterized and its role in cardiac pacemaking has been investigated.^[1]^[2]^[3] Among the unusual features which justified the name "funny" were a mixed Na+ and K+ permeability, activation on hyperpolarization, and very slow kinetics.^[1]

Function

The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrioventricular node (AVN) and the Purkinje fibres of conduction tissue. The funny current is a mixed sodium–potassium current that activates upon hyperpolarization at voltages in the diastolic range (normally from −60/−70 mV to −40 mV). When at the end of a sinoatrial action potential, the membrane repolarizes below the I_f threshold (about −40/−50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD); by this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate.

Another unusual feature of I_f is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to f-channels and increase their open probability.^[4] cAMP dependence is a particularly relevant physiological property, since it underlies the I_f-dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP-molecules which bind to f-channels and shift the I_f activation range to more positive voltages; this mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration. Parasympathetic stimulation (which acts to increase probability of potassium channels opening but decreases the probability of calcium channel opening) decreases the heart rate by the opposite action, that is by shifting the I_f activation curve towards more negative voltages.

Related currents

A similar current, termed I_h, has also been described in different types of neurons where it has a variety of functions, including the contribution to control of rhythmic firing, regulation of neuronal excitability, sensory transduction, synaptic plasticity and more.

Molecular determinants

The molecular determinants of the pacemaker current belong to the HCN channel (hyperpolarization-activated cyclic nucleotide–gated channel), of which 4 isoforms (HCN1 to HCN4) are known. Based on their sequence, HCN channels are classified as members of the superfamily of voltage-gated K⁺ (Kv) and CNG channels.^[3]^[5]

Clinical significance

Ivabradine

Because of their relevance to generation of pacemaker activity and modulation of spontaneous frequency, f-channels are natural targets of drugs aimed to pharmacologically control heart rate. Several agents called "heart rate reducing agents" act by specifically inhibiting f-channel function.^[3] Ivabradine is the most specific and selective I_f inhibitor and the only member of this family that is now marketed for pharmacological treatment of chronic stable angina in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. Recent studies have also indicated that funny channel inhibition can be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients with heart rate ≥70 bpm.^[6]^[7]

Cardiovascular diseases represent a major cause of worldwide mortality, and the relevance of the genetic component in these diseases has recently become more apparent. Genetic alterations of HCN4 channels (the molecular correlate of sinoatrial f-channels) coupled to rhythm disturbances have been reported in humans. For example, an inherited mutation of a highly conserved residue in the CNBD of the HCN4 protein (S672R) is associated with inherited sinus bradycardia.^[8] In vitro studies indicate that the S672R mutation causes a hyperpolarizing shift of the HCN4 channel open probability curve of about 5 mV in heterozygosis, an effect similar to the hyperpolarizing shift caused by parasympathetic stimulation and able to explain a reduction of inward current during diastole and the resulting slower spontaneous rate.

Biological pacemakers, generally intended as cell substrates able to induce spontaneous activity in silent tissue, represent a potential tool to overcome the limitations of electronic pacemakers. One of the strategies used to generate biological pacemakers involves the use of cells inherently expressing or engineered to express funny channels. Different types of stem cells can be used for this purpose.^[5]

References

1 2 Brown, H. F., DiFrancesco, D., Noble, S. J. (1979). How does adrenaline accelerate the heart? Nature, 280, 235-236.
↑ DiFrancesco, D., Ojeda, C. (1980). Properties of the current i_f in the sino-atrial node of the rabbit compared with those of the current iK, in Purkinje fibres. Journal of Physiology, 308, 353-367.
1 2 3 Baruscotti, M., Bucchi, A., DiFrancesco, D. (2005). Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacology & Therapeutics, 107, 59-79.
↑ DiFrancesco, D., Tortora, P. (1991). Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature, 351, 145-147.
1 2 Barbuti, A., Baruscotti, M., DiFrancesco, D. (2007). The pacemaker current: from basics to the clinics. Journal of Cardiovascular Electrophysiology, 18, 342-347
↑ Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators (2008)Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 372(9641):807-16
↑ Beautiful Study Group, Ferrari R, Ford I, Fox K, Steg PG, Tendera M.(2008)The BEAUTIFUL study: randomized trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction – baseline characteristics of the study population. Cardiology.110(4):271-82
↑ Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D. (2006). Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. The New England Journal of Medicine, 354, 151-157.

Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3

Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ

Proton-gated	Amiloride-sensitive cation channel 1 2 3 4

Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1

Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1

Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18

Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker gene

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B

H⁺: Proton channel	HVCN1

M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4

M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6

H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family

Cytoplasm: Gap junction	Connexin: A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4) Innexin

By gating mechanism

Ion channel class	Ligand-gated Light-gated Voltage-gated Stretch-activated

see also disorders

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