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Historical Note Regarding the Discovery of the Na/Ca Exchanger and the PMCA

As indicated in the Preface to this volume, this meeting celebrated the 40th anniversary of the discovery of the two Ca2+ extrusion mechanisms. Na/Ca exchange was discovered simultaneously and independently in Mainz, Germany by Harald Reuter, and in Plymouth, England by Peter F. Baker and Mordecai P. Blaustein, in the autumn of 1966. In September 1966, Richard Steinhardt and Mordy Blaustein traveled to the marine laboratory at Plymouth (with Baker, who worked across the hall) to explore the activation of the squid axon Na+ pump by external cations. Within a month, they had uncovered a large ouabain-insensitive (and thus non-Na+pump-mediated) Na+ efflux in Na+-free Li+-containing medium. This efflux was dependent on external Ca2+, suggesting that it involved an exchange of Na+ for Ca2+.1 Baker pointed out the parallels with Rolf Niedergerke’s observations on Na+-dependent Ca2+ movements in the frog heart.2 The reading of the article by Niedergerke convinced Blaustein that cardiac muscle also had an Na/Ca exchange system and that this was the missing link between Na+ pump inhibition and the cardiotonic action of digitalis.3,4 At the very same time, Harald Reuter was studying Na/Ca exchange in mammalian cardiac muscle.5 Blaustein met Reuter at the International Physiological Congress in Washington in 1968. They subsequently agreed to work together in 1971 in Bern, Switzerland, where they studied Na/Ca exchange in vascular smooth muscle. Their manuscript, in which they alluded to the possible role of Na/Ca exchange in hypertension, was rejected by Nature and Science.4 Although he was on the sidelines, compared to Blaustein and Reuter, Denis Noble met Reuter in 1966 at a course in Homburg/Saar, Reuter being a student and Noble a lecturer.6 It was at that course that Reuter was stimulated to look for an Na/Ca exchanger.4 That same year, Hans Jurg Schatzmann published his paper in Experiencia;7 it was a little masterpiece, both from scientific and writing points of view.8