Setsuro Ebashi (1922–2006) E

NEWS & VIEWS NATURE|Vol 442|31 August 2006

OBITUARY

Setsuro Ebashi (1922–2006) E. PHILPOTT D. Physiologist who uncovered the regulatory role of calcium in cells.

All animal movement depends on muscle calcium — causes relaxation. Ebashi contractions. Nerve impulses cause a change compared the calcium-binding activity of of electrical potential across the muscle-cell various chelating agents with their relaxing membrane, which rapidly propagates to activity and found that they correlated both ends of the cell, causing contraction. exactly. He further showed that fragmented How electrical excitation at the muscle sarcoplasmic reticulum can accumulate cell’s surface induces contraction of the calcium ions rapidly in the presence of ATP, proteins packed inside was one of the biggest and so can remove enough calcium from the mysteries in physiology for decades. It was surrounding medium to cause relaxation. Setsuro Ebashi, who died on 17 July 2006 The relaxation process is the reverse of at the age of 83, who essentially solved this contraction, so Ebashi proposed what is conundrum. our current understanding of excitation– Muscle cells contain two types of filament contraction coupling: excitation at the that are aligned along the long axis of the cell. surface membrane somehow sends a signal Contraction occurs when the protein myosin to the sarcoplasmic reticulum; this releases Ebashi really broke open the field of calcium in the ‘thick’ filaments reacts with another the calcium ions that accumulate there signalling, and profoundly influenced life protein, actin, in the ‘thin’ filaments, causing during the relaxing and resting period, science as a whole. the filaments to slide across each other, pulling and the flood of calcium ions induces the Setsuro Ebashi was brilliant from the ends of the cell closer together. The process contractile reaction. childhood. He skipped a year in both primary is fuelled by the breakdown of ATP. The Examining the process more closely, Ebashi and middle schools and was admitted into the biochemical basis of contraction was largely discovered that purified myosin and actin Dai-ichi High School, the most prestigious determined by Albert Szent-Györgyi in the react with ATP even in the complete absence high school in Japan at the time. He was 1940s, and the biophysical and structural basis of calcium ions, and that the regulatory action promoted to be professor of pharmacology was uncovered by Jean Hanson and Hugh of calcium is exerted only in the presence of at the University of Tokyo at the age of 36. Huxley, and by Andrew Huxley and a certain protein factor. This factor turned But his scientific success was not only due to R. Niedergerke, during the 1950s. But how out to be a mixture of tropomyosin, a protein his sharp mind — he worked extremely hard the process was triggered by nerves remained that previously had no known function, and a in the laboratory, until after midnight most a mystery. newly discovered protein that Ebashi named nights. Although he had many collaborators, Ebashi discovered that in the absence of troponin. Tropomyosin and troponin are most notably his wife Fumiko Ebashi, all the calcium ions, no contractile reaction occurs, present with actin in the thin filaments . In major results were, amazingly, produced by even when ATP is added to the myosin–actin the absence of calcium ions, the two proteins Ebashi himself. system, but that with even a minute amount cooperate to inhibit actin, preventing it from As one of the most respected scientists in of calcium (of the order of 1 micromolar), interacting with myosin in the thick filaments. physiology and pharmacology worldwide, ATP induces a vigorous contractile Having found that calcium binds strongly to Ebashi received numerous honours, including reaction. This calcium-dependence had troponin, Ebashi proposed that the resulting the Order of Cultural Merit, the highest been previously overlooked by biochemists conformational changes in troponin are scientific honour in Japan. He was a Member because of low-level contamination from transmitted through tropomyosin to actin of the Japan Academy and a Foreign Member laboratory glassware and impurities in the to remove the inhibition, and the contractile of the Royal Society in London, and of chemical reagents. Ebashi took tremendous reaction ensues — a mechanism that has several other academies, including those of pains to avoid contamination by calcium ions subsequently been confirmed. the United States, Germany and Belgium. in all the solutions and protein preparations In the early 1960s, the idea that a simple He also contributed to the global scientific he used, making his results unequivocal. inorganic ion such as calcium controls community as president of the International His work was consistent with contemporary contraction was not popular among most Union for Pure and Applied Biophysics results from Annemarie Weber, who showed biochemists — the prevailing belief was that (1978–81) and the International Union of independently that the breakdown of ATP such an important biological phenomenon Pharmacology (1990–94), and presided over during the contractile reaction requires as contraction should be regulated by the International Congress of Pharmacology minute amounts of calcium. sophisticated organic molecules. So Ebashi held in Tokyo in 1981. The idea that calcium might be involved in had a hard time getting his ideas taken Ebashi was a man of attractive personality: muscle contraction came to Ebashi during seriously, despite his clear evidence. charismatic, warm-hearted, helpful and his studies on the ‘relaxing factor’ reported by Only after the discovery of troponin and loyal to his colleagues, and patriotic to his B. B. Marsh in 1951. This was a fraction of the his elucidation of the mechanism did country. Despite suffering physical handicaps homogenate that is made when muscle cells everybody accept the regulatory role of following a stroke in 2000, he kept a clear are ground up, and it could induce relaxation calcium ions. mind, and because his condition was fairly of the myosin–actin system. Ebashi proved The regulatory roles of calcium are stable, nobody expected his sudden death. All that relaxing factor is nothing but fragmented not confined to muscle contraction. his friends and pupils greatly lament it. ■ pieces of a muscle-specific organelle called Since Ebashi’s discovery, numerous Makoto Endo the sarcoplasmic reticulum. Enquiring into cellular processes, including the release of Makoto Endo is in the Department of the factor’s mechanism of action, Ebashi got neurotransmitters and hormones, metabolic Pharmacology, University of Tokyo, 7-3-1, a hint from Emil Bozler’s result in 1954 that switching and gene expression, have been Bunkyo-ku, Tokyo 113-0033, Japan. EDTA — a ‘chelating’ agent that sequesters found to be controlled by calcium. Thus, e-mail: makoendo@ gakushikai.jp