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Am J Physiol Cell Physiol 287: C1165-C1166, 2004; doi:10.1152/classicessays.00008.2004 Free Article
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EDITORIAL FOCUS

ESSAYS ON APS CLASSIC PAPERS

Ca-induced Ca release: lessons regarding cell models

David R. Harder

Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

ABSTRACT

This essay looks at the historical significance of an APS classic paper that is freely available online:

Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol Cell Physiol 245: C1—C14, 1983 (http://ajpcell.physiology.org/cgi/reprint/245/1/C1).

THIS MONOLOG is part of an APS series on major findings that have shaped many of our present concepts regarding what we currently understand as physiology. The process of Ca-induced Ca release was a topic of much discussion and debate when first introduced. The seminal manuscript on this topic is often considered that of Alexandre Fabiato, "Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum," from 1983. In this paper and those leading up to it, Fabiato and others used a "skinned fiber" preparation in which the plasma membrane is chemically removed. The hypothesis is as follows: as a myocyte is activated, the entry of Ca into the cell induces a release of Ca from the sarcoplasmic reticulum (SR). The amount of Ca released from the SR is proportional to the amount and rate of change of Ca as the cell is activated. Following an initial rapid increase in release of Ca from the SR, this release process shuts down, thereby allowing the SR to refill its Ca stores. The initial release of Ca is from channels in the SR, which are subject to many properties of ion channels in general. For example, as the Ca gradient increases, movement through the channel slows down due to the concentration and charge.

Since these early studies, much has been learned about the physiological significance of Ca-induced Ca release. One of the early problems was use of a model that could isolate the functional elements but ignored the seemingly (at the time) unimportant elements. With respect to the skinned fiber, the major missing elements included the plasma membrane and cytosolic components removed in the process. The importance of the plasma membrane and other cellular components on Ca-induced Ca release has been elucidated since single cell studies. For example, ions such as strontium and the quantity of Ca initially in the cell have marked effects of electromechanical coupling (EC) via Ca-induced Ca release (Spencer et al., Ref. 2). Experiments such as these demonstrate how movement of Ca into the cell, through the plasma membrane, affects the kinetics of Ca release from the SR.

It is worthwhile to discuss how model systems used to study mechanisms of cellular function by their very nature are both necessary and flawed. Necessary, because to understand mechanisms such as how the release of Ca from cardiac SR is controlled, it is necessary to isolate the SR and eliminate confounding effects of other cellular structures. Flawed, in that by eliminating specific cellular effects of other cellular structures, it is not possible to understand the integrated physiological significance of a specific mechanism. The model approach is essential, but eventually requires the context of the cell and organism. This paradigm has been used with great utility throughout physiology and with great success. Problems arise, however, when the "whole" is not put in context, and mechanisms are based in "pieces" only.

Ca entering the cell through L-type channels in the sarcolemma is known to activate ryanodine receptors regulating Ca release and reload channels in the SR. The process of filling the SR requires ATP. By shutting down release of Ca from the SR, the cell is able to more efficiently fill this compartment using minimum energy. The entire process of surging intracellular Ca concentration is far more efficient than a simple influx of Ca from the extracellular space through L-type Ca channels. This is one of the pivotal mechanisms of cardiac function and regulation of EC coupling. Our understanding of the mechanisms of Ca-induced Ca release has allowed us to understand much of the pharmacology that changes the level and sensitivity of EC coupling in the cardiac myocyte. Many drugs work through actions on SR Ca release rather than ion influx via Ca channels. In fact, the SR is also a critical player in the rapid uptake of Ca to initiate sarcolemmal relaxation via the SR Ca-ATPase.

Many anesthetic agents act by reducing Ca flux through L-type channels and reducing the amount of Ca stored in the SR. Similarly, positive inotropic agents regulate the force of contraction partially through regulation of Ca from the SR or in combination of intracellular Ca levels via channels. Pathophysiological alterations in the SR uptake and release may represent focus points in the basis of cardiovascular disease. Our understanding of the mechanisms of Ca-induced Ca release has served as a cornerstone with respect to defining the mechanism of EC coupling and the effects of intracellular Ca. This is truly one of the pivotal physiological findings within the physiological literature regarding cardiac function.



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  		Fig. 1. Alexandre Fabiato. Courtesy of Dr. Alexandre Fabiato.

 
FOOTNOTES


Address for correspondence: D. R. Harder, Professor and Director of Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 (E-mail: dharder{at}mail.mcw.edu)

REFERENCES

1. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol Cell Physiol 245: C1–C14, 1983.[Abstract/Free Full Text]

2. Spencer CL, Barsotti RJ, and Berlin JR. Loading of calcium and strontium into the SR in rat ventricular muscle. J Mol Cell Cardiol 32: 1285–300, 2000.[Medline]




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This Article
Free upon publication Free Article
Right arrow Abstract Freely available
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Right arrow Alert me when this article is cited
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PubMed
Right arrow Articles by Harder, D. R.

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