Funny current
Encyclopedia
Funny current refers to a specific current in the heart
.
First described in the late 1970s in Purkinje fibers and sinoatrial myocytes, the cardiac pacemaker "funny" (If) current has been extensively characterized and its role in cardiac pacemaking has been investigated.
(SAN, the natural pacemaker region), the atrio-ventricular 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 controls the rate of spontaneous activity of sinoatrial myocytes, 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. 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 reduces cAMP) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages (Fig 1).
) 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 channels.
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
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. 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.
Funny current seems a term quite close to a diastolic EKG if inexpensively and reproducibly captured by other researchers. Most authorities believe Diastole
to be a passive relaxation phase. Work regarding Funny Current is important and suggests an electrical backswing to the forward electrical drive visible on the EKG if the electrical signature of Systole
QRS Interval (medicine] is dampened for a better view of the following ST Segment
. Most neurological study of the heart illuminates Systole
under Sympathetic
influence. Funny Current is likely an illumination of Parasympathetic electrical influence in Diastole
.
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
.
First described in the late 1970s in Purkinje fibers and sinoatrial myocytes, the cardiac pacemaker "funny" (If) current has been extensively characterized and its role in cardiac pacemaking has been investigated.
Function
The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial nodeSinoatrial node
The sinoatrial node is the impulse-generating tissue located in the right atrium of the heart, and thus the generator of normal sinus rhythm. It is a group of cells positioned on the wall of the right atrium, near the entrance of the superior vena cava...
(SAN, the natural pacemaker region), the atrio-ventricular node
Atrioventricular node
The atrioventricular node is a part of the electrical control system of the heart that coordinates heart rate. It electrically connects atrial and ventricular chambers...
(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
Diastolic depolarization
In mammals cardiac electrical activity originates from specialized myocytes of the sinoatrial node which generate spontaneous and rhythmic action potentials . The unique functional aspect of this type of myocyte is the absence of a stable resting potential during diastole...
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 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. 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 reduces cAMP) decreases the heart rate by the opposite action, that is by shifting the If activation 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 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 Hyperpolarization-activated Cyclic Nucleotide-gated channels family (HCN, see HCN channelHCN channel
Hyperpolarization-activated cyclic nucleotide-gated channels are proteins that serve as ion channels across the plasma membrane of heart and brain cells. HCN channels are sometimes referred to as “pacemaker channels” because they help to generate rhythmic activity within groups of heart and brain...
) 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 channels.
Clinical significance
Ivabradine
Ivabradine
Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris. It is marketed under the trade name Procoralan , Coralan in India , Australia or such as in Italy Corlentor , and was also known as S-16257 during its development...
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. 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.
Funny current seems a term quite close to a diastolic EKG if inexpensively and reproducibly captured by other researchers. Most authorities believe Diastole
Diastole
Diastole is the period of time when the heart fills with blood after systole . Ventricular diastole is the period during which the ventricles are relaxing, while atrial diastole is the period during which the atria are relaxing...
to be a passive relaxation phase. Work regarding Funny Current is important and suggests an electrical backswing to the forward electrical drive visible on the EKG if the electrical signature of Systole
Systole
Systole may refer to:*Systole , a term describing the contraction of the heart*Systolic array, a term used in computer architecture*Systolic geometry, a term used in mathematics...
QRS Interval (medicine] is dampened for a better view of the following ST Segment
ST segment
In electrocardiography, the ST segment connects the QRS complex and the T wave and has a duration of 0.08 to 0.12 sec .It starts at the J point and ends at the beginning of the T wave...
. Most neurological study of the heart illuminates Systole
Systole
Systole may refer to:*Systole , a term describing the contraction of the heart*Systolic array, a term used in computer architecture*Systolic geometry, a term used in mathematics...
under Sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
influence. Funny Current is likely an illumination of Parasympathetic electrical influence in Diastole
Diastole
Diastole is the period of time when the heart fills with blood after systole . Ventricular diastole is the period during which the ventricles are relaxing, while atrial diastole is the period during which the atria are relaxing...
.