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The pacemaker current (or I''f'', or IK''f'', also referred to as the funny current) is an
electric current An electric current is a stream of charged particles, such as electrons or ions, moving through an electrical conductor or space. It is measured as the net rate of flow of electric charge through a surface or into a control volume. The moving pa ...
in the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
that flows through the
HCN channel Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated ion channel, voltage-gated cation ion channel, channels in the plasma membranes of heart and brain cells. H ...
or pacemaker channel. Such channels are important parts of the
electrical conduction system of the heart The cardiac conduction system (CCS) (also called the electrical conduction system of the heart) transmits the signals generated by the sinoatrial node – the heart's pacemaker, to cause the heart muscle to contract, and pump blood through the ...
and form a component of the natural pacemaker. First described in the late 1970s in
Purkinje fibers The Purkinje fibers (; often incorrectly ; Purkinje tissue or subendocardial branches) are located in the inner ventricular walls of the heart, just beneath the endocardium in a space called the subendocardium. The Purkinje fibers are specia ...
and
sinoatrial The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approxima ...
myocytes A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...
, the cardiac pacemaker "funny" (If) current has been extensively characterized and its role in cardiac pacemaking has been investigated. Among the unusual features which justified the name "funny" are mixed Na+ and K+ permeability, activation on hyperpolarization, and very slow kinetics.


Function

The funny current is highly expressed in spontaneously active cardiac regions, such as the
sinoatrial node The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...
(SAN, the natural pacemaker region), the
atrioventricular node The atrioventricular node or AV node electrically connects the heart's atria and ventricles to coordinate beating in the top of the heart; it is part of the electrical conduction system of the heart. The AV node lies at the lower back section of t ...
(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 If threshold (about −40/−50 mV), the funny current is activated and supplies inward current, which is responsible for starting the
diastolic depolarization In mammals, cardiac electrical activity originates from specialized myocytes of the sinoatrial node (SAN) which generate spontaneous and rhythmic action potentials (AP). The unique functional aspect of this type of myocyte is the absence of a stable ...
phase (DD); by this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, and thus the cardiac rate. Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides.
Cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP) molecules bind directly to f-channels and increase their open probability. cAMP dependence is a particularly relevant physiological property, since it underlies the If-dependent autonomic regulation 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 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 If activation curve towards more negative voltages. When vagally-released acetylcholine (ACh) binds to muscarinic M2 receptors, which promotes dissociation of βγ subunit complexes, leading to direct opening of the G-protein–gated inwardly rectifying K+ channel (Girk/Kir) ''IKACh.''


Related currents

A similar current, termed Ih (hyperpolarization-activated), 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 (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated ion channel, voltage-gated cation ion channel, channels in the plasma membranes of heart and brain cells. H ...
( hyperpolarization-activated
cyclic nucleotide A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, a ...
–gated channel), of which 4
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
(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.


Clinical significance

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.
Ivabradine Ivabradine, sold under the brand name Procoralan among others, is a medication, which is a funny current (I''f'') inhibitor, used for the symptomatic management of heart-related chest pain and heart failure. Patients who qualify for use of Ivab ...
is the most specific and selective If 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. 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 Sinus bradycardia is a sinus node dysfunction giving a heart rate that is lower than the normal 60–100 beats per minute (bpm) in humans. Bradycardia is generally defined to be a heart rate of under 60 bpm. Signs and symptoms The decreased hear ...
. ''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 pacemaker An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart eith ...
s. 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.


See also

*
Pacemaker potential In the pacemaking cells of the heart (e.g., the sinoatrial node), the pacemaker potential (also called the pacemaker current) is the slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end ...
*
Cardiac pacemaker 350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart. The_muscle_contraction.htm ...
*
Cardiac action potential The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...


References

{{DEFAULTSORT:Funny Current Cardiac electrophysiology