ORCiD

0000-0002-6489-4651

Document Type

Article

Publication Title

The Journal of General Physiology

ISSN

1540-7748

Volume

116

Issue

6

DOI

10.1085/jgp.116.6.873

First Page

873

Last Page

882

Publication Date

12-1-2000

Abstract

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.

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Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License