Ryanodine Receptor Adaptation

In the heart, depolarization during the action potential activates voltage-dependent Ca2+ channels that mediate a small, localized Ca2+ influx (ICa). This small Ca2+ signal activates specialized Ca2+ release channels, the ryanodine receptors (RyRs), in the sarcoplasmic reticulum (SR). This process is called Ca2+-induced Ca2+ release (CICR). Intuitively, the CICR process should be self-regenerating because the Ca2+ released from the SR should feedback and activate further SR Ca2+ release. However, the CICR process is precisely controlled in the heart and, consequently, some sort of negative control mechanism(s) must exist to counter the inherent positive feedback of the CICR process. Defining the nature of this negative control has been a focus of investigation for decades. Several mechanisms have been suggested including all of the following: Ca2+-dependent inactivation, adaptation, stochastic attrition, “fateful” inactivation, SR Ca2+ depletion, and coupled RyR gating. These mechanisms are generally regarded as being mutually exclusive (i.e., alternative). An emerging and more sophisticated view is that the required negative control is probably provided by a synergy of mechanisms, not a single mechanism. In this perspective, we focus on the origin of Ca2+-dependent inactivation and adaptation of single cardiac RyR channels. Specific concerns about the adaptation phenomenon are addressed and a comprehensive unifying view of RyR Ca2+ regulation is forwarded. We conclude that the steady-state Ca2+ dependence, high Ca2+ inactivation and low Ca2+ adaptation are three distinct manifestations of the same underlying mechanism, Ca2+-dependent modal RyR channel gating

In Silico Simulations Reveal That Ryr Distribution Affects the Dynamics of Calcium Release in Cardiac Myocytes

The dyads of cardiac myocytes contain ryanodine receptors (RYRs) that generate calcium sparks upon activation. To test how geometric factors of RYR distribution contribute to the formation of calcium sparks, which cannot be addressed experimentally, we performed in silico simulations on a large set of models of calcium release sites (CRSs). Our models covered the observed range of RYR number, density, and spatial arrangement. The calcium release function of CRSs was modeled by RYR openings, with an open probability dependent on concentrations of free Ca2+ and Mg2+ ions, in a rapidly buffered system, with a constant open RYR calcium current. We found that simulations of spontaneous sparks by repeatedly opening one of the RYRs in a CRS produced three different types of calcium release events (CREs) in any of the models. Transformation of simulated CREs into fluorescence signals yielded calcium sparks with characteristics close to the observed ones. CRE occurrence varied broadly with the spatial distribution of RYRs in the CRS but did not consistently correlate with RYR number, surface density, or calcium current. However, it correlated with RYR coupling strength, defined as the weighted product of RYR vicinity and calcium current, so that CRE characteristics of all models followed the same state-response function. This finding revealed the synergy between structure and function of CRSs in shaping dyad function. Lastly, rearrangements of RYRs simulating hypothetical experiments on splitting and compaction of a dyad revealed an increased propensity to generate spontaneous sparks and an overall increase in calcium release in smaller and more compact dyads, thus underlying the importance and physiological role of RYR arrangement in cardiac myocytes. © 2021 Iaparov et al.The research was supported by Russian Foundation for Basic Research according to research project no. 18-31-00153 (development of the computational model of CRS); by the Government of the Russian Federation (program 02.A03.21.0006); by the Ministry of Science and Higher Education of the Russian Federation (project no. FEUZ-2020-0054); by the Slovak Research and Development Agency (project APVV-15-0302); by SAV-TUBITAK (project JRP/2019/836/RyRinHeart); and by the Operational Program Integrated Infrastructure for the project “Long-term strategic research of prevention, intervention, and mechanisms of obesity and its comorbidities,” ITMS: 313011V344, co-financed by the European Regional Development Fund. The authors declare no competing financial interests

A minimal gating model for the cardiac calcium release channel.

A Markovian model of the cardiac Ca release channel, based on experimental single-channel gating data, was constructed to understand the transient nature of Ca release. The rate constants for a minimal gating scheme with one Ca-free resting state, and with two open and three closed states with one bound Ca2+, were optimized to simulate the following experimental findings. In steady state the channel displays three modes of activity: inactivated 1 mode without openings, low-activity L mode with single openings, and high-activity H mode with bursts of openings. At the onset of a Ca2+ step, the channel first activates in H mode and then slowly relaxes to a mixture of all three modes, the distribution of which depends on the new Ca2+. The corresponding ensemble current shows rapid activation, which is followed by a slow partial inactivation. The transient reactivation of the channel (increment detection) in response to successive additions of Ca2+ is then explained by the model as a gradual recruitment of channels from the extant pool of channels in the resting state. For channels in a living cell, the model predicts a high level of peak activation, a high extent of inactivation, and rapid deactivation, which could underlie the observed characteristics of the elementary release events (calcium sparks)