From Wikipedia, the free encyclopedia Funny current
Funny current
Funny current (or funny channel or If, or IKf, or pace-
current)
channel,
maker current refers to a specific current in the heart.
Molecular determinants
First described in the late 1970s in Purkinje fibers and The molecular determinants of the pacemaker current
sinoatrial myocytes, the cardiac pacemaker "funny" (If) belong to the Hyperpolarization-activated Cyclic
current has been extensively characterized and its role in Nucleotide-gated channels family (HCN, see HCN chan-
cardiac pacemaking has been investigated.[1][2][3] nel) of which 4 isoforms (HCN1-4) are known. Based on
their sequence, HCN channels are classified as members
of the superfamily of voltage-gated K+ (Kv) and CNG
Function channels.[3][5]
The funny current is highly expressed in spontaneously
active cardiac regions, such as the sinoatrial node (SAN,
the natural pacemaker region), the atrio-ventricular
Clinical significance
node (AVN) and the Purkinje fibres of conduction tissue.
Particularly unusual, the funny current is a mixed
sodium-potassium current, inward and slowly activating
on 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 If 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 con-
trols the rate of spontaneous activity of sinoatrial my-
ocytes, hence the cardiac rate.
Another unusual feature of If 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 prop-
erty, since it underlies the If –dependent autonomic reg-
ulation of heart rate. Sympathetic stimulation raises the
level of cAMP molecules which bind to f-channels and
shift the If activation range to more positive voltages;
this mechanism leads to an increase of the current at di-
astolic voltages and therefore to an increase of the steep-
ness of DD and heart rate acceleration. Parasympathetic
stimulation (which reduces cAMP) decreases the heart
rate by the opposite action, that is by shifting the If acti-
vation curve towards more negative voltages (Fig 1).
Related currents
A similar current, termed Ih, has also been described in
different types of neurons where it has a variety of func-
tions, including the contribution to control of rhythmic
Ivabradine
firing, regulation of neuronal excitability, sensory trans-
duction, synaptic plasticity and more.
Because of their relevance to generation of pacemaker
activity and modulation of spontaneous frequency, f-
channels are natural targets of drugs aimed to pharmaco-
1
From Wikipedia, the free encyclopedia Funny current
logically control heart rate. Several agents called "heart mination of Parasympathetic electrical influence in Dias-
rate reducing agents" act by specifically inhibiting f- tole.
channel function.[3] Ivabradine is the most specific and
selective If inhibitor and the only member of this family
that is now marketed for pharmacological treatment of
See also
chronic stable angina in patients with normal sinus • Pacemaker potential
rhythm who have a contraindication or intolerance to • Cardiac pacemaker
beta-blockers. Recent studies have also indicated that • Cardiac action potential
funny channel inhibition can be used to reduce the inci-
dence of coronary artery disease outcomes in a subgroup
of patients with heart rate ≥70 bpm.[6][7]
References
Cardiovascular diseases represent a major cause of [1] Brown, H. F., DiFrancesco, D., Noble, S. J. (1979).
worldwide mortality, and the relevance of the genetic How does adrenaline accelerate the heart? Nature,
component in these diseases has recently become more 280, 235-236.
apparent. Genetic alterations of HCN4 channels (the mol- [2] DiFrancesco, D., Ojeda, C. (1980). Properties of the
ecular correlate of sinoatrial f-channels) coupled to current if in the sino-atrial node of the rabbit
rhythm disturbances have been reported in humans. For compared with those of the current iK, in Purkinje
example an inherited mutation of a highly conserved fibres. Journal of Physiology, 308, 353-367.
residue in the CNBD of the HCN4 protein (S672R) is asso- [3] ^ Baruscotti, M., Bucchi, A., DiFrancesco, D. (2005).
ciated with inherited sinus bradycardia.[8] In vitro stud- Physiology and pharmacology of the cardiac
ies indicate that the S672R mutation causes a hyperpo- pacemaker ("funny") current. Pharmacology &
larizing shift of the HCN4 channel open probability curve Therapeutics, 107, 59-79.
of about 5 mV in heterozygosis, an effect similar to the [4] DiFrancesco, D., Tortora, P. (1991). Direct activation
hyperpolarizing shift caused by parasympathetic stimu- of cardiac pacemaker channels by intracellular
lation and able to explain a reduction of inward current cyclic AMP. Nature, 351, 145-147.
during diastole and the resulting slower spontaneous [5] ^ Barbuti, A., Baruscotti, M., DiFrancesco, D. (2007).
rate. The pacemaker current: from basics to the clinics.
Biological pacemakers, generally intended as cell sub- Journal of Cardiovascular Electrophysiology, 18,
strates able to induce spontaneous activity in silent tis- 342-347
sue, represent a potential tool to overcome the limita- [6] Fox K, Ford I, Steg PG, Tendera M, Ferrari R;
tions of electronic pacemakers. One of the strategies used BEAUTIFUL Investigators (2008)Ivabradine for
to generate biological pacemakers involves the use of patients with stable coronary artery disease and
cells inherently expressing or engineered to express fun- left-ventricular systolic dysfunction (BEAUTIFUL):
ny channels. Different types of stem cells can be used for a randomised, double-blind, placebo-controlled
this purpose.[5] trial. Lancet. 372(9641):807-16
Funny current seems a term quite close to a diastolic [7] Beautiful Study Group, Ferrari R, Ford I, Fox K, Steg
EKG if inexpensively and reproducibly captured by other PG, Tendera M.(2008)The BEAUTIFUL study:
researchers. Most authorities believe Diastole to be a pas- randomized trial of ivabradine in patients with
sive relaxation phase. Work regarding Funny Current is stable coronary artery disease and left ventricular
important and suggests an electrical backswing to the systolic dysfunction – baseline characteristics of
forward electrical drive visible on the EKG if the electri- the study population. Cardiology.110(4):271-82
cal signature of Systole QRS Interval (medicine] is damp- [8] Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T.,
ened for a better view of the following ST Segment. Most DiFrancesco, D. (2006). Familial sinus bradycardia
neurological study of the heart illuminates Systole under associated with a mutation in the cardiac
Sympathetic influence. Funny Current is likely an illu- pacemaker channel. The New England Journal of
Medicine, 354, 151-157.
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Categories:
• Cardiac electrophysiology
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