Calcium Rules
Authors: Cecilia Hidalgo
Journal: Circulation (2017)

ow does a person pen 1200 words on "calcium rules" when a search for "calcium" in PubMed produces >530 000 references, 15 000 of which are from 2016 alone?To face this challenge, I decided to recount my life's journey unveiling some of these rules, a journey that has led me to conclude that this versatile element, so important to the central processes of life, does in fact rule the cell.I first became acquainted with the calcium ion (Ca 2+ ) in the mid-1960s when I studied Ca 2+ efflux from the squid giant axon under the guidance of Eduardo Rojas in Montemar, Chile.In 1968, we reported that this complex process exhibits metabolism-dependent components controlled by mitochondrial function.Squid seasons were short, precluding us from testing, as planned, the effects of removing external sodium (Na + ) on Ca 2+ efflux.Thus, we missed the discovery of the Na + -Ca 2+ -exchanger reported in the late 1960s by Reuter and Seitz in cardiac muscle and in the squid axon by Peter Baker and colleagues.What did we know then about Ca 2+ rules?From the pioneering studies of Sydney Ringer, we were aware that heart contraction required Ca 2+ , but the underlying mechanisms emerged many years later.In the early 1960s, for instance, 3 independent research teams led by Wilhelm Hasselbach in Germany, Setsuro Ebashi in Japan, and Annemarie Weber in the United States reported Ca 2+ uptake by the sarcoplasmic reticulum and discovered the sarcoplasmic reticulum calcium pump, later known as the sarco/endoplasmic reticulum calcium ATPase pump.They also showed conclusively that an increase in intracellular Ca 2+ concentration promotes Ca 2+ binding to troponin C, which allows the actin-myosin interaction that triggers muscle contraction (for historical aspects, see ref. 1).Later studies by many groups on the workings of the sarco/ endoplasmic reticulum calcium ATPase pump, including analysis of its crystal structure and our own studies of how the physical state of the lipids surrounding the pump control its rotational motion and activity, provided key information regarding the mechanisms underlying the active transport of ions across biological membranes.Shortly after, several groups reported that Ca 2+ also governed cardiac muscle contraction.Before long, we learned that the mechanisms underlying excitationcontraction coupling exhibited similar characteristics in skeletal and cardiac muscle but also displayed some significant differences; the use of selective blockers of voltage-gated Ca 2+ channels allowed significant progress in this regard.Central among these differences was the finding that Ca 2+ entry by voltage-gated Ca 2+ channels causes the cytoplasmic Ca 2+ increase elicited by the cardiac action potential, whereas contraction of skeletal muscle fibers proceeds in the absence of Ca 2+ entry.In addition, several early reports showed that the Na + -Ca 2+ -exchanger plays a key role in cardiac contraction, and that phospholamban, an intrinsic membrane protein absent from the sarcoplasmic reticulum of fast-twitch skeletal muscle, tightly controls the cardiac sarco/endoplasmic reticulum calcium ATPase pump. 2 In the early 1960s, a few studies reported that by carrying out Ca 2+ uptake and release, mitochondria played a role in cellular Ca 2+ signaling. 1In subsequent years, Calcium Rules