Ryanodine Receptor Adaptation

In the heart, depolarization during the action potential activates voltage-dependent Ca²⁺ channels that mediate a small, localized Ca²⁺ influx (I_Ca). 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,...