JTV-519 (K201) is a 1,4-benzothiazepine derivative that interacts with many cellular targets. It has many structural similarities to

diltiazem Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...

, a Ca²⁺ channel blocker used for treatment of

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

, angina pectoris and some types of arrhythmias. JTV-519 acts in the sarcoplasmic reticulum (SR) of cardiac myocytes by binding to and stabilizing the

ryanodine receptor Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...

(RyR2) in its closed state. It can be used in the treatment of cardiac arrhythmias,

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

catecholaminergic polymorphic ventricular tachycardia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur du ...

(CPVT) and store overload-induced Ca²⁺ release (SOICR). Currently, this drug has only been tested on animals and its side effects are still unknown. As research continues, some studies have also found a dose-dependent response; where there is no improvement seen in failing hearts at 0.3 μM and a decline in response at 1 μM. Treatment with JTV-519 involves stabilization of RyR2 in its closed state, decreasing its open probability during

diastole Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are re-filling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventric ...

and inhibiting a Ca²⁺ leak into the cell's cytosol. By decreasing the intracellular Ca²⁺ leak, it is able to prevent Ca²⁺ sparks or increases in the resting membrane potential, which can lead to spontaneous depolarization (cardiac arrhythmias), and eventually

, due to the unsynchronized contraction of the atrial and ventricular compartments of the heart. When Ca²⁺ sparks occur from the SR, the increase in intracellular Ca²⁺ contributes to the rising membrane potential which leads to the irregular heart beat associated to cardiac arrhythmias. It can also prevent SOICR in the same manner; preventing opening of the channel due to the increase of Ca²⁺ inside the SR levels beyond its threshold.

Molecular problem

In the closed state, N-terminal and central domains come into close contact interacting to cause a “zipping” of domains. This leads to conformational constraints that stabilize the channel and maintain the closed state. Most RyR2 mutations are clustered into three regions of the channel, all affecting the same domains that interact to stabilize the channel. Any of these mutations can lead to “unzipping” of the domains and a decrease in the

energy barrier In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules p ...

required for opening the channel (increasing its open probability). This channel “unzipping” allows for an increase in protein kinase A

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

and calstabin2 dissociation. Phosphorylation of RyR2 increases the channel's response to Ca²⁺, which usually binds the RyR2 to open it. If the channel become phosphorylated, this can lead to an increase in Ca²⁺ sparks due to an increase in Ca²⁺ sensitivity. Some researchers believe that the depletion of calstabin2 from the RyR2 causes the calcium leak. The depletion of calstabin2 can occur in both heart failure and CPVT. Calstabin2 is a protein that stabilizes RyR2 in its closed state, preventing Ca²⁺ leakage during diastole. When calstabin2 is lost, the interdomain interactions of RyR2 become loose, allowing the Ca²⁺ leak. However, the role of calstabin2 has been controversial, as some studies have found it necessary for the effect of JTV-519, whereas others have found the drug functions without the stabilizing protein.

Molecular mechanism

JTV-519 seems to restore the stable conformation of RyR2 during the closed state. It is still controversial whether or not calstabin2 is necessary for this process, however, many studies believe that JTV-519 can act directly on the channel and by binding, prevents conformational changes. This stabilization of the channel decreases its open probability resulting in fewer leaks of Ca²⁺ into the cytosol and fewer Ca²⁺ sparks to occur. Researchers who believe that calstabin2 is necessary for JTV-519 effect, found that this drug may function by inducing the binding of calstabin2 back to the channel or increasing calstabin2's affinity for the RyR2 and thus increasing its stability.

References

{{reflist Calcium channel blockers Benzothiazepines Phenol ethers Piperidines