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Cardiovascular Research 2001 52(1):8-13; doi:10.1016/S0008-6363(01)00405-9
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Copyright © 2001, European Society of Cardiology

A growth of ideas: Role of calcium as activator of cardiac contraction

Arnold M Katz*

Cardiology Division, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA

arnold.m.katz{at}dartmouth.edu

* Address for correspondence: 1592 New Boston Road, P.O. Box 1048, Norwich, VT 05055-1048, USA. Tel.: +1-802-649-3947; fax: +1-802-649-1746

Received 11 June 2001; accepted 13 June 2001


   1. Introduction
Top
 1. Introduction
2. Role of calcium...
 3. Interactions of calcium...
 4. Calcium removal from...
 5. Cardiac plasma membrane...
 6. Conclusions
 References
 
A role for calcium as activator of cardiac contraction was first suggested in 1883, when Ringer observed that hearts placed in a calcium-free solution ceased to beat [1]. This was an accidental discovery that occurred when Ringer’s technician used distilled water, rather than the water supplied by the New River Water Company, in studies of isolated frog hearts. Ringer analyzed the ‘pipe water’, and found that it contained ‘minute traces of various inorganic substances’. When he tested the ability of different salts to support cardiac contraction, Ringer not only identified the ability of calcium to restore cardiac contraction, but also found that this effect was antagonized by potassium [2]. As described below, the negative inotropic effect of potassium was to confuse investigators more than a half century later.

It took almost 80 years before the major systems responsible for the activating effect of calcium on the heart came into focus. This brief history provides a personal view of several of the discoveries between 1883 and the 1960s that made it possible to explain Ringer’s seminal observation.


   2. Role of calcium in the activation of muscle contraction
Top
 1. Introduction
 2. Role of calcium...
3. Interactions of calcium...
 4. Calcium removal from...
 5. Cardiac plasma membrane...
 6. Conclusions
 References
 
The slow pace at which science moved in the early 20th century is seen in the fact that 30 years elapsed between Ringer’s first report and the next logical experiment. This experiment, reported by Mines in 1913, showed that although the heart cannot contract in a calcium-free solution, it does generate an electrical signal [3]. Mines’ study, by demonstrating that calcium is not essential for electrical signaling at the cell surface, suggested instead that this ion might serve as a direct activator of the contractile process within the cell. However, another 30 years were to pass before methods were developed that could test this hypothesis directly.

Demonstration of the ability of increased cytosolic calcium to activate the contractile machinery required methods that allow various substances to be injected directly into living muscle cells. This occurred during the 1930s and early 1940s, when several investigators obtained evidence that calcium serves as this physiological trigger [4–6]. However, credit for this discovery is generally given to Heilbrunn and Wiercinski, who in 1947 reported that among several physiologically significant cations injected into the interior of muscle cells, only calcium elicited a contraction [7]. Another example of the leisurely pace of research at that time is provided by the fact that 4 years earlier, in 1943, Heilbrunn (referring to unpublished observations) wrote in his Outline of General Physiology:

...if various cations are injected into muscle fibers, the effect of the calcium ion [to activate contraction] is outstanding. Even a solution as dilute as m/1500 calcium chloride produces a marked effect. (It should be noted that the calcium must be injected into the muscle fiber, for exposure of the of the uninjured fiber surface to calcium has no effect.) [8].

Demonstration that increased cytosolic calcium stimulates contraction, of course, provided no information as to how calcium gets into the cell, how increased cytosolic calcium causes the muscle to contract, or how calcium is removed from the cytosol to allow the muscle to relax. These questions were not answered until the 1960s, when major discoveries were made in three areas of biochemistry and biophysics. These were the mechanism of the physiological interactions of calcium with the contractile proteins; the role of the sarcoplasmic reticulum in taking up, storing and releasing calcium; and the existence of plasma membrane calcium channels that allow this cation to enter the myocardial cell.


   3. Interactions of calcium with the contractile proteins
Top
 1. Introduction
 2. Role of calcium...
 3. Interactions of calcium...
4. Calcium removal from...
 5. Cardiac plasma membrane...
 6. Conclusions
 References
 
3.1 Pitfalls in studying the interactions of calcium with actomyosin
In the early 1960s, more than a decade after the discovery that a rise in intracellular calcium initiated muscular contraction, the mechanism remained a mystery. Three problems made it difficult to explain this activating effect. The first was that calcium salts have two quite different effects on actomyosin; at low (micromolar) concentrations calcium is the physiological activator, but the increased ionic strength caused by high concentrations of calcium salts dissociate actin and myosin and so cause the contractile proteins to relax. The second problem arose because calcium is a ubiquitous contaminant, often approaching levels of 10 µM which fully activate the contractile proteins. For this reason, unless a calcium chelator like EGTA is used to lower ionized calcium concentrations, the physiological activating effect is already present, even when no calcium is added. The third problem was that the highly purified actomyosin preparations used by careful investigators in the 1960s generally lacked the regulatory tropomyosin–troponin complex, and so remained fully activated even at submicromolar calcium concentrations.

I fell into all three of these pitfalls in 1962 when, as a research fellow with Wilfried Mommaerts at UCLA, I began to study the cardiac contractile proteins. Having spent a year comparing highly purified contractile proteins from cardiac and skeletal muscle, I thought I was in an excellent position to study reconstituted actomyosin. My initial studies used the actins and myosins that I had meticulously purified from rabbit white skeletal muscle, which was the standard preparation used by investigators throughout the world. I first tried to identify an activating effect of calcium by adding 10–100 mM calcium chloride, and so only saw the inhibitory response caused by increased ionic strength. After I realized my error, I sought to inhibit actin–myosin interactions by lowering ionized calcium concentration with a calcium chelator. Once again I was unsuccessful because, as I soon realized, an essential component was missing from my contractile protein preparations.

3.2 Role of tropomyosin in regulating actin–myosin interactions
In the summer of 1962, when I had begun to study reconstituted actomyosins, I was also comparing the physicochemical properties of cardiac and skeletal tropomyosins [9], which at the time had no known function [10,11]. One hot Los Angeles evening, while taking a shower, the idea jumped into my head that the missing calcium-sensitizing factor might be tropomyosin. Accordingly, I added purified tropomyosin to my actomyosins and, to my delight, found that this protein could inhibit the interactions between actin and myosin. After spending almost a year characterizing the complex effects of tropomyosin on actomyosin, in the late summer of 1963 I presented my findings for the first time in a research seminar at UCSF. Although my description of the effects of tropomyosin was greeted with interest, there was no excitement. In the first place, while I had shown that tropomyosin was a regulator, I had not found that it conferred calcium-sensitivity to actomyosin. More important, Ebashi had given a seminar at UCSF a few weeks earlier in which he described a tropomyosin-containing protein preparation that did restore calcium-sensitivity to actomyosin [12]. This last news, of course, stimulated me to publish my results as quickly as possible. Accordingly, I sent a short, single-authored paper to Biochemical and Biophysical Research Communications, then one of the first ‘rapid publication’ journals. However, my paper was rejected on 19 November, 1993 (I still have the letter) with the comment:

While the Editors felt your observations were interesting, they thought that publication at this time would be premature and that additional experiments would, in the long run, make it more meaningful to the general public.

As I had more than a year’s worth of ‘additional experiments’, it was easy for me to expand my paper. I resubmitted a more detailed manuscript to Biochemical and Biophysical Research Communications, and on 6 December 1963 the paper came back with the comment:

The Editors and referees still felt, on reading your revised manuscript, that it would be more appropriate to publish this material as part of a more complete and full-length publication.

This, of course, illustrates a well known reality: while an established figure can publish a new idea as a rapid communication, and an unknown can publish a small advance on an old idea, it is often viewed as presumptuous for a newcomer to try to publish a new idea. I did, however, submit my tropomyosin data to the Sixth International Congress of Biochemistry, where I presented my data in the summer of 1964, and these findings were published in a full-length paper later that year [13].

3.3 The discovery of troponin
At the International Congress of Biochemistry in 1964, it became clear that several investigators had been studying the ability of several tropomyosin-containing protein mixtures to sensitize the contractile proteins to calcium. Some found that tropomyosin itself could confer calcium-sensitivity, but others (including myself) could not find this effect. This gave rise to a debate as to whether denaturation explained why some tropomyosins failed to sensitize actomyosin to calcium, or whether, instead, something in addition to tropomyosin was needed to confer calcium sensitivity.

A clue to the correct answer had been published in 1961 by Weber and Winicur [14], who commented that the calcium-sensitivity of reconstituted actomyosins, which varied from experiment to experiment, seemed to depend in some way on the actin preparations. Having learned from Mommaerts that the purest actins were obtained by extracting acetone powders made from minced muscle at 0°C, rather than at room temperature, I suspected that my reconstituted actomyosins were insensitive to the activating effect of calcium because an important component was missing from the actin. A second clue came from an informal discussion with John Gergely and Wilhelm Hasselbach, who told me that tropomyosin co-purified with actin when the acetone powders were extracted at room temperature. This chance conversation led me to study actomyosins reconstituted with ‘room temperature’ actins, which unlike ‘cold’ actins, yielded calcium-sensitive actomyosins. I was then able to purify a calcium-sensitizing factor from the ‘room temperature’ actins, which I found contained not only tropomyosin, but also a new proline-rich globular protein that I called ‘P2’ (second precipitate) [15]. In 1965, while gathering these data, I wrote to Ebashi telling him of my evidence that another protein, along with tropomyosin, was needed to sensitize actomyosin to calcium. Ebashi’s gracious reply included the manuscript of his then unpublished paper describing a protein that he had named ‘troponin’ [16], along with the suggestion that this might be the same as my P2. The rest is history; within 5 years, many groups described tropomyosin-containing calcium-sensitizing factors [17–22], and Endo’s pioneering work (and much better choice of a name) defined the role of the tropomyosin–troponin complex in rabbit skeletal muscle [23].

These studies provided the foundation that allowed me to define the role of calcium in regulating the cardiac contractile systems. Having spent almost 5 years characterizing the calcium-sensitizing systems in skeletal muscle, it was a simple matter to apply this line of research to the heart, By 1968, I was able to show that the cardiac contractile proteins were also regulated by troponin and tropomyosin [24].


   4. Calcium removal from the cytosol: role of the sarcoplasmic reticulum
Top
 1. Introduction
 2. Role of calcium...
 3. Interactions of calcium...
 4. Calcium removal from...
5. Cardiac plasma membrane...
 6. Conclusions
 References
 
The second of the biochemical discoveries that defined the role of calcium in regulating myocardial contractility was that an internal membrane system, the sarcoplasmic reticulum, regulated cytosolic calcium concentration. Like the story of troponin, this discovery has a convoluted history.

As soon as the appearance of calcium in the cytosol was recognized to stimulate contraction, attention turned to possible mechanisms by which this effect could be reversed. In the early 1950s, only a few years after Heilbrunn and Weircinsky described the stimulating effect of calcium, Marsh [25] and Bendall [26] examined the possibility that muscle extracts contained a ‘factor’ that could reverse this effect. These experiments yielded positive results; supernatants obtained when muscle minces were subjected to the highest speed centrifugation then available were found to relax contractile protein preparations in vitro, and this relaxing effect could be abolished by addition of calcium. However, the initial interpretations of these findings missed the mark as the relaxing effect of these supernatants was believed to be due to the actions of a ‘soluble relaxing factor’ that was inactivated by calcium (for review, see Ref. [27]). Accordingly, subsequent research sought to identify the ‘soluble relaxing factor’. Among the more interesting candidates was cyclic AMP, whose role as a regulator of cellular function had just been discovered [28]. Initial data from Mommaerts’ laboratory suggested that cyclic AMP was the physiological relaxing factor [29]; however, within a few months, this suggestion had to be retracted [30]. I have little doubt that these two papers, which were published in 1963 in Biochemical and Biophysical Research Communications, contributed to the rejection of my tropomyosin paper by that journal (see above).

A more substantial clue to the nature of the ‘soluble relaxing factor’ came from evidence that the relaxing effect was potentiated by ATP and phosphocreatine, findings that were initially interpreted to mean that the high energy phosphate compounds themselves were the relaxing factor. However, other studies failed to confirm this hypothesis, so that for almost a decade, this field was in a state of confusion.

The nature of the ‘soluble relaxing factor’ became clear in the early 1960s, when this factor was found not to be soluble! This discovery was made possible when development of high speed ultracentrifuges revealed that membrane vesicles, called microsomes, were present in the supernatants obtained when muscle homogenates were subjected to lower speed centrifugation. In the early 1960s, Hasselbach et al. [31] and Ebashi and Lippman [32] were able to demonstrate that these membrane vesicles, when energized by ATP, sequestered calcium. This meant that the effects of the ‘soluble relaxing factor’ occurred when these membrane vesicles utilized the energy derived from ATP to remove calcium from the contractile proteins. These membranes, which were quickly recognized to be derived from the sarcoplasmic reticulum, were subsequently found to contain an ATP-dependent calcium pump that relaxed muscle by transporting calcium uphill, out of the cytosol.

In 1966, faced with an increasing number of investigators engaged in the study of the cardiac contractile proteins, I decided to turn my attention to the cardiac sarcoplasmic reticulum. It required less than a year for my group [33], and subsequently Harigaya and Schwartz [34], to demonstrate that the calcium pump of the cardiac sarcoplasmic reticulum had both the capacity and velocity to relax the heart.


   5. Cardiac plasma membrane calcium channels
Top
 1. Introduction
 2. Role of calcium...
 3. Interactions of calcium...
 4. Calcium removal from...
 5. Cardiac plasma membrane...
6. Conclusions
 References
 
The third major discovery regarding the role of calcium as activator of cardiac contraction was that variations in the amount of calcium that entered the cell play a major role in regulating myocardial contractility. I did not work in this field, so that the following description is provided to complete my story.

Although Ringer had shown that calcium is essential for the heart to contract (see above), for more than 75 years the mechanism by which extracellular calcium influences structures inside cardiac myocardial cells was not understood. This mystery was compounded by the fact that skeletal muscle, unlike the heart, is able to contract in calcium-free media. Key to understanding the role of extracellular calcium was the discovery, in the early 1960s, that stimulation of the heart increases calcium influx across the plasma membrane [35–37]. However, a physiological role for this calcium influx in generating the cardiac action potential seemed doubtful because action potentials recorded in nerve and skeletal muscle (then the standard models for electrophysiologists) could be explained by electrogenic sodium and potassium fluxes across the plasma membrane. In fact, the view that calcium fluxes across the plasma membrane contributed to the cardiac action potential was sometimes viewed as heretical.

The discovery in the late 1960s of an inward calcium current across the plasma membrane [38,39] that was proportional to myocardial contractility [40] overthrew the then canonical view that sodium and potassium currents alone explained the cardiac action potential. This discovery also completed a story that began in 1871, when Bowditch described the positive inotropic effect of increased heart rate [41]. This phenomenon, which Bowditch called the positive staircase (in German treppe), was readily explained when it was recognized that the increased frequency of calcium channel openings at faster heart rates admitted a greater amount of calcium to the cell interior. An additional role for this calcium entry was subsequently identified when Fabiato found that calcium release from the cardiac sarcoplasmic reticulum is stimulated by the small influx of calcium across the plasma membrane (‘calcium-triggered calcium release’ [42]). This process, which is key to cardiac excitation–contraction coupling, differs from that in skeletal muscle, where excitation–contraction coupling depends on a mechanical coupling rather than calcium entry (for review see Ref. [43]).

Another element in the elucidation of the actions of extracellular calcium was the discovery of this sodium/calcium exchanger, which uses energy made available by the sodium gradient across the plasma membrane to remove calcium from the cytosol. Discovery of this antiport was stimulated by a puzzling observation, reported in 1948, that contractility in frog hearts is proportional to the ratio between extracellular sodium and calcium [44]. Subsequent work led to the suggestion that a sodium/calcium exchanger carries either of these ions in either direction across the plasma membrane [45]. At about the same time, sodium was found to be pumped out of the cell in exchange for potassium by a membrane pump that utilizes energy derived from ATP hydrolysis [46]. The role of this sodium/potassium ATPase in establishing a sodium gradient that can be used to transport calcium out of the cell helped explain the inotropic action of digitalis, which resolved one of the oldest problems in cardiology. Evidence that the sodium pump is inhibited by cardiac glycosides [47,48] led Repke, in 1964, to propose that increased cytosolic sodium increases myocardial contractility by competing with calcium for efflux from the myocardium via the sodium/calcium exchanger, thereby increasing intracellular stores of calcium [49].

During the late 1950s and early 1960s the negative inotropic effect of extracellular potassium, which had been described by Ringer in 1884 (see above), was interpreted by many to mean that changes in cytosolic potassium concentration contribute directly to the regulation of myocardial contractility [50]. However the overwhelming evidence that calcium regulates contractility which had accumulated by the late 1960s, along with the demonstration that sodium and potassium have similar effects on the cardiac contractile proteins [51], made it clear that the negative inotropic effect of increasing extracellular potassium is indirect, being mediated largely by effects on resting potential that alter excitability.

By the end of the 1960s, therefore, the major systems that allow calcium to regulate myocardial contractility had come into focus. Two important gaps, the properties of the intracellular calcium release channels that allow calcium to leave the sarcoplasmic reticulum [52], and the existence of a plasma membrane calcium ATPase that, along with the sodium/calcium exchanger, pumps calcium out of the cell [53], were filled in the 1980s.


   6. Conclusions
Top
 1. Introduction
 2. Role of calcium...
 3. Interactions of calcium...
 4. Calcium removal from...
 5. Cardiac plasma membrane...
 6. Conclusions
References
 
This brief history, which documents the accelerating pace of discovery in cardiovascular science, shows how progress has depended on the development of appropriate methodology and on the interplay between concepts which originated in laboratories throughout the world. It is clear that elucidation of the mechanisms by which calcium regulates cardiac contraction was relatively simple when compared to the intricacy of today’s science. The value in learning about the century between 1871, when Bowditch described the staircase phenomenon, and 1969, when I chose to end the present narrative lies in the fact that the process of discovery has not changed. Reading this relatively simple history can therefore provide important lessons that may help in understanding the vastly more complex discoveries being made today.


   References
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 1. Introduction
 2. Role of calcium...
 3. Interactions of calcium...
 4. Calcium removal from...
 5. Cardiac plasma membrane...
 6. Conclusions
 References
 

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