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The Role of Calcium in Heart Failure

By Robin Arnette
November 2007

Distinguished Lecture Andrew Marks
Distinguished Lecture Andrew Marks (Photo courtesy of Steve McCaw)
Lecture host Jim Putney, an authority on calcium signaling
Lecture host Jim Putney, an authority on calcium signaling (Photo courtesy of Steve McCaw)
Marks' lecture drew a capacity crowd to the Rodbell Auditorium
Marks' lecture drew a capacity crowd to the Rodbell Auditorium (Photo courtesy of Steve McCaw)

As part of the 2007-2008 Distinguished Lecture Series, NIEHS researchers were treated to an engaging discourse on the role of calcium in heart failure by Andrew R. Marks, M.D., professor and chairman of the Department of Physiology and Cellular Biophysics at the Columbia University College of Physicians and Surgeons. His lecture, titled "Defective Calcium Regulation as a Cause of Heart Failure and Sudden Cardiac Death," took place on October 9 in Rodbell Auditorium. James Putney, Ph.D., head of the Calcium Regulation Group in the Laboratory of Signal Transduction, hosted the seminar.

Marks began by reminding the audience that heart failure is the leading cause of death in the U.S. and the developed world. The condition afflicts about 5 million patients in the U.S., with nearly half a million new diagnoses each year. Sudden cardiac death, a closely related disorder, claims about half a million American lives annually, with over 60% of all patients with some form of heart disease dying suddenly. Marks said that for decades physicians never understood why tissue biopsied from hearts that had undergone heart failure looked normal under the microscope.

The answer, he proposed, has to do with defective calcium regulation during excitation-contraction coupling. Marks said excitation-contraction coupling occurs during each heart beat and every time a person moves a limb.

"When muscle membranes-both skeletal and cardiac-become depolarized or electrically activated, an electrical signal travels down the transverse tubule where it activates a voltage-dependent calcium channel in the transverse tubule," Marks explained. "Calcium then binds to the calcium release channel, made up of four monomers of ryanodine receptors (RyR), releasing a much larger store of calcium from the sarcoplasmic reticulum, which causes the contractile filaments to contract. Relaxation occurs when the calcium is pumped back into the sarcoplasmic reticulum."

Marks said it was critical that the RyR channels stay tightly closed during times that muscles are relaxed. If not, calcium can leak and the individual could have a defect in moving the limbs or allowing the heart to relax to refill for the next contraction.

In the late '80s in collaboration with protein chemist Paul Temps, Marks cloned the ryanodine receptor and also discovered a smaller protein, which subsequent experiments led him to call the calcium channel-stabilizing binding protein or calstabin. "We expressed ryanodine receptor in SF9 insect cells, one of only a few types of cell that don't express calstabin, isolated the ryanodine receptor channel and measured the channel's activity," Marks said. "In the absence of calstabin, the channel leaked calcium and never stayed in the open or closed state." In contrast, when Marks co-expressed calstabin with the ryanodine receptor, the calstabin fixed the "leakiness" because the ryanodine receptor demonstrated long and stable closed states.

Once Marks knew that calstabin stabilized the ryanodine receptor, he wanted to understand the mechanism of action. It turned out that the process was involved in the classic fight or flight stress response. Marks' group determined that cyclic-dependent protein kinase A (PKA) phosporylated one serine residue within the ryanodine receptor (Ser2808), but since four ryanodine receptors make up the ion channel, three or perhaps all four of the Ser2808s may be phosphorylated.

This hyperphosporylation state, which occurs in damaged hearts, depletes the calstabin, thereby destabilizing the channel and causing the calcium leak. "Over time this depletes the precious pool of calcium in the sarcoplasmic reticulum and instead of increasing contractility, you decrease cardiac output," Marks declared. "These events have been associated as molecular triggers of ventricular arrhythmias [alteration in heart rhythm]."

Using Drug Therapy to Prevent Heart Failure

Beta-blockers, one of the most widely prescribed drugs in the world, fix the calcium leak in ryanodine receptors by preventing PKA activity, but the drugs also block all phosphorylation events in the body, some of which are necessary for proper function. Therefore, Marks and his team started with JTV-519-a compound synthesized by Japanese chemists during the development of diltiazem (Cardizem), the highly used calcium channel blocker-and synthesized over 440 chemical derivatives. These compounds fix the leak in RyR channels by preventing the depletion of the calstabin from the PKA-hyperphosphorylated ryanodine receptor by causing a conformational change of the receptor. Marks and his group named them rycals or calcium channel stabilizers and have since created a company at Columbia to mass produce oral versions of the derivatives. Clinical trials using rycals will begin in April 2008.

"These compounds are 100 percent specific to the ryanodine receptor and are water soluble," Marks stated. "A Japanese group, using another mammalian heart failure model, has confirmed that rycals improve cardiac function, fix the calcium leak and restore calstabin binding to the ryanodine receptor. We are very proud of our work because it may help millions of patients with heart disease."

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