ORIGINAL ARTICLE © Copyright 2006 by Humana Press Inc. All rights of any nature whatsoever reserved. 1085-9195/06/44:251–271/$30.00 Cell Biochemistry and Biophysics 251 Volume 44, 2006 INTRODUCTION It is widely appreciated that Ca 2+ ions are central reg- ulators of biological activities, including muscle contrac- tion, secretion, cell fusion, blood clotting, fertilization, and control of intermediary metabolism (1–5). The role of Ca 2+ in muscle contraction has been recognized since the historic finding of Ringer that Ca 2+ was required for the beating of isolated frog hearts (6). Other milestone experiments include the finding that Ca 2+ injected into skeletal muscle causes contraction, and that the sar- coplasmic reticulum (SR) plays a central role in both the release and reuptake of Ca 2+ . In its reuptake role, the SR was first identified as the “relaxing factor.” Its role in Ca 2+ release in skeletal muscle means that this intracel- lular vesicle is the immediate source of trigger Ca 2+ to support contraction (7). The latter point was the source of much debate, because it was widely believed that an extracellular to intracellular flow must be the sequence leading to an increased cytosolic Ca 2+ (8). This belief was predicated on the immense gradient of extracellular to cytosolic Ca 2+ . Extracellular Ca 2+ concentration is on the order of millimolar; cytosolic Ca 2+ concentration ranges from a resting value of 0.1 µM to a stimulated value of about 1 µM. Thus, in the resting state, there is a concentration gradient of approx 10,000. However, skeletal muscle contracts in the absence of external Ca 2+ , so that for this tissue, the contractile Ca 2+ signal is clearly of intracellu- lar origin, a pool now identified as the SR (7–9). For other cell types, the mechanism of Ca 2+ flows is not so clear, and there remains a strong contingent of opinion in favor of extracellular Ca 2+ entry for signaling. Still, for nonstriated muscle and many other cell types, the endo- plasmic reticulum (ER) store is used for Ca 2+ release, triggered by IP 3 (10,11). Extracellular Ca 2+ entry could conceivably be important for triggering cell responses, for refilling intracellular stores, or both. In this article, we will examine the evidence for the pathway of Ca 2+ flows in skeletal muscle cells, and in others, to determine how Ca 2+ is released into the cytosol to stimulate the contrac- tile event, how Ca 2+ enters the cells, and Ca 2+ accumula- tion in the ER and mitochondria. A New Hypothesis for Ca 2+ Flows in Skeletal Muscle and Its Implications for Other Cell Types Mohammad Naimul Islam and Raymond S. Ochs* Department of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439. Abstract We offer a new hypothesis to explain calcium flows in skeletal muscle cells. Our model accounts for the uptake of Ca 2+ from the extracellular fluid, and the release of Ca 2+ from the sarcoplasmic reticulum (SR/ER) (the endoplasmic reticulum in muscle is named sarcoplasmic reticulum); this has engendered difficulty in reviews encompassing both muscle and nonmuscle cells. Here we will typically refer to the organelle as ER, except when specifically discussing muscle cells. The broad consideration of two major, still unexplained properties of skele- tal muscle function, namely excitation contraction coupling and capacitative calcium entry are accounted for in a unitary hypothesis. This model allows a reinterpretation of existing data, and points to areas where new inves- tigation may be fruitful. While primarily aimed at explaining Ca 2+ flows in skeletal muscle, we consider find- ings of other systems to explore the implications of this hypothesis for other cell types. Index Entries: Capacitative calcium entry; store operated calcium entry; excitation contraction coupling; skeletal muscle; heart cell; dihydropyridine receptor; L-channel; ryanodine receptor. * Author to whom all correspondence and reprint requests should be addressed. E-mail: ionophore@gmail.com