“We went back to fundamentals to finally answer this question,” said Donald Bers, chair of the UC Davis Department of Pharmacology and the principal investigator of the study, published in the June issue of Circulation Research. “Because of our findings, investigators can now focus on exploring other aspects of heart physiology to define the cellular foundations of arrhythmia.”
Bers’ study focused on intracellular calcium-release channels known as ryanodine receptors (RyR) and, in particular, the channel found in heart muscle called RyR2 that provides the normally well-controlled calcium signal that activates a regular heart beat. In certain heart conditions, RyR2 can release calcium out of sync and trigger cardiac arrhythmias. A controversy has swirled about whether or not a small RyR2-bound protein called FKBP12.6 can cause these arrhythmias by dissociating from RyR2 during sympathetic stimulation, which makes the heart beat too rapidly.
Bers and his team developed new confocal fluorescence imaging techniques to visualize simultaneously the binding of FKBP12.6 to RyR2 and arrhythmogenic calcium-release events in live cardiac myocytes obtained from rats. They found that the binding of FKBP12.6 to RyR2 does have a slight stabilizing effect on RyR2 function, but that massive sympathetic stimulation had absolutely no effect on the binding of FKBP12.6 to RyR2.
Moreover, said Bers, “We found that FKBP12.6 is present in such low concentrations compared to RyR2 that most RyR2 channels cannot possibly be regulated by FKBP12.6. Our search for understanding of how calcium-dependent cardiac arrhythmias occur in the diseased heart must now focus on other mechanisms.”
The study was unique in that FKBP12.6 binding and unbinding properties were measured in multiple ways in the natural heart-cell environment. All outcomes yielded comparable results, strengthening the veracity of the finding. Bers’ research should finally put to rest the question of the role of FKBP12.6 in calcium dysregulation, according to an editorial that accompanies the article.
“In a superb series of experiments in cardiac myocytes, these authors show FKBP12.6 (the putative RyR2 stabilizer) is found in much lower abundance than RyR,” wrote Steven R. Houser of the Temple University School of Medicine in Philadelphia, Pa. “The authors should be commended because they developed the novel, quantitative techniques that were needed to directly address critical controversies related to RyR.”
Bers and his team will continue to study the role of RyR2 in heart failure and arrhythmias. This field of research still has many puzzles that, once solved, will lead to the discovery of new therapies and pharmaceuticals for heart disease.
“We know that RyR2 channels are involved in heart arrhythmias, but it’s clearly not due to the loss of FKBP12.6 binding,” he said. “Looking elsewhere for the cause will guide us more quickly toward effective ways to treat heart failure.”
Other study authors were Tao Guo, Emmanuel Camors, Yi Yang and Eckard Picht of the Department of Pharmacology at UC Davis; Razvan L. Cornea and Bradley R. Fruen of the Department of Biochemistry, Molecular Biology and Biophysics at the University of Minnesota, Minneapolis; and Sabine Huke of the Division of Clinical Pharmacology at Vanderbilt University School of Medicine in Nashville, Tenn.
The UC Davis Department of Pharmacology brings together experts in the biochemical, molecular, cellular and integrative aspects of modern pharmacology to characterize the mechanisms by which information is transferred from the extracellular environment to influence cellular function and nuclear transcription and to develop methods and reagents that will interfere with or enhance that information transfer. Department faculty have expertise in ion channels, molecular and cellular neurobiology, functional genomics and proteomics, transcription and gene regulation, cell signaling and cardiovascular health. For information, visit the department’s website.