Calcium-triggered arrhythmias are known to result when intracellular calcium stores rise above a certain threshold. The calcium ion channels switch from shut to open, and a dangerous “calcium wave” may be unleashed. This process, called spontaneous store overload-induced calcium release (SOICR), causes the heart to beat irregularly, and may even lead to sudden death. Because the potential consequences of SOICR are so dire, scientists have long studied the phenomenon, hoping to explain its underlying molecular mechanism. Now, scientists based at the University of Calgary and Alberta Health Service’s Libin Cardiovacular Institute report that they have found an important clue. It concerns a calcium-sensing gate within the ryanodine receptor, a cardiac calcium release channel also known as RyR2.

The scientist published their results January 19 in Nature Medicine, in an article entitled “The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias.” In this article, the authors write that “the RyR2’s helix bundle crossing (its proposed gate) encompasses an essential component of the store/luminal Ca2+ sensing mechanism that controls SOICR and thus Ca2+ triggered [ventricular tachyarrhythmias]. This store Ca2+ sensing gate also governs normal luminal Ca2+ regulation of RyR2 and EC coupling gain. Thus, this uniquely positioned store Ca2+-sensing mechanism plays an important role in both health and disease.”

Besides confirming that RyR2 has a role in the initiation of calcium waves and calcium-triggered arrhythmias, the scientists implicate a particular part of RyR2—the E4872 residue, which is located in the helix bundle crossing. This residue, the scientists propose, acts as a kind of sensor and is essential for luminal Ca2+ activation. According to the scientists, “when luminal Ca2+ associates with E4872, the inter-subunit electrostatic interactions between residues D4868/E4872/R4874 are disrupted, and this increases the likelihood that the channel transitions from the closed to open state.”

Using a genetically modified mouse model, the scientists were able to manipulate the sensor and completely prevent calcium-triggered arrhythmias: “Pharmacological agents that reduce RyR2 open time suppress Ca2+ waves and Ca2+ triggered [ventricular tachyarrhythmias]. Interestingly, the E4872Q mutation also reduced the duration of RyR2 openings, decreased SOICR likelihood, and completely suppressed [ventricular tachyarrhythmias] in [catecholaminergic polymorphic ventricular tachycardia (CPVT)-prone] mouse hearts.”

The study also pointed out that “residues D4868, E4872, and R4874 are conserved in all types of RyRs and IP3Rs, implying that this store sensing gate structure may be a common feature of Ca2+ release channels.” So, not only is the sensor mechanism susceptible to manipulation, it is also highly conserved. Together, these facts suggest that “the RyR2 store Ca2+ sensing gate a potential therapeutic target for anti-arrhythmic therapies.”

“The calcium-sensing gate mechanism discovered here is an entirely novel concept with potential to shift our general understanding of ion channel gating, cardiac arrhythmogenesis, and the treatment of calcium-triggered arrhythmias,” said S.R. Wayne Chen, Ph.D., the study’s senior author and University of Calgary–Libin Institute researcher. “These findings open a new chapter of calcium signaling, and the discovery fosters the possibilities of new drug interventions.”
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