Jens Christian Skou

The sodium–potassium pump is the principal mechanism for active ion transport across the cellular membrane of cardiac tissue. Vital for numerous bodily processes such as nerve cell signalling, heart contractions or kidney function, for example, it is responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients which is crucial for cardiac cell electrophysiology. Consequently, in a range of diseases, sodium–potassium pump activity is impaired, such as in ischaemia and heart failure. A key stage of the knowledge breakthrough in this field came with the work of Professor Jens Christian Skou with his discovery of the enzyme sodium, potassium-stimulated adenosine triphosphatase (Na+, K+-ATPase), the enzyme that maintains the balance of sodium and potassium ions in the living cell, and for which in 1997 he received a half share of the Nobel Prize for Chemistry. The other half share of the prize went to Professor Paul D. Boyer of the University of California in Los Angeles and Dr John E. Walker from the Medical Research Council Laboratory of Molecular Biology at Cambridge in the UK, for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP). In honouring their work, the Nobel committee said: ‘The three laureates have performed pioneering work on enzymes that participate in the conversion of the “high-energy” compound adenosine triphosphate’. Adenosine triphosphate, which functions as a universal carrier of energy in all living organisms—including plants, animals, and humans—captures the chemical energy released by the combustion of nutrients and transfers it to reactions that require energy. First discovered by the German chemist Karl Lohmann in 1929, its structure was later clarified, and synthesized chemically by the Scottish Nobel laureate of 1957 Alexander Todd. Boyer had begun his studies of ATP formation in the early 1950s, endeavouring to find out by isotope techniques how ATP synthase functions and particularly how it uses energy to create new ATP. Meanwhile, Walker made his first studies of ATP synthase at the beginning of the 1980s with the starting point being that a detailed chemical and structural knowledge of an enzyme is required to understand in detail how it functions. He determined the amino acid sequences of the constituent protein units, and the atomic structure of the catalytic part of the enzyme and deduced that the nATP synthase operated by a remarkable rotary mechanism, churning out 60 kg of ATP per day in each human being to sustain their lives. Skou was born on 8 October 1918, in Lemvig in the west of Denmark to Magnus and Ane-Margrethe Skou. The eldest of four children, his father ran a timber and coal merchants. Having developed an enthusiasm for science at school, Jens enrolled to study medicine at the University of Copenhagen in 1937 and received his medical degree in the summer of 1944, at a time that his country was occupied by Germany, with a view to a career in surgery. He worked on a surgical ward before obtaining a position at the Orthopaedic Hospital in Aarhus but decided to stop his clinical training in 1947 for a position at the Institute for Medical Physiology at Aarhus University to write his doctoral thesis on the anaesthetic and toxic mechanism of action of local anaesthetics, while also working as a doctor on call one night a week. From receiving his doctoral degree at Aarhus University in 1954, he had become so enthused about research that he decided to give up surgery altogether and continue with his scientific work. His research interests shifted from anaesthesia to cell membrane physiology and the active transport of cations in biological cells, which ultimately led to the discovery of the sodium–potassium pump Na+,K+-ATPase. Skou had been searching for an ATP-degrading enzyme in the nerve membrane that could be associated with ion transport, and in 1957, he published the first article on an ATPase, which was activated by sodium and potassium ions (Na+,K+-ATPase). He was the first to describe an enzyme that can promote transport of substances through a cell membrane, having discovered an enzyme—Na+,K+-ATPase—that serves as a biological pump to transport ions. He made the discovery while studying the leg nerve membranes of shore crabs. He saw that the ATP-degrading enzyme found in the preparation required the presence of magnesium ions and was stimulated with increasing quantities of sodium ions up to a certain limit. It was that work which led him to conclude that an enzyme in the body serves as a kind of pump that regulates the amount of potassium and sodium ions inside cells. With the movement of ions being the basis for many bodily functions such as nerve impulses, muscle contractions, and digestion, Skou’s findings were to form a cornerstone of understanding of how the body works. From the publication of the 1957 paper, his scientific interest shifted from the ‘effect of local anaesthetics to active transport of cations’. In his further studies of the enzyme mechanism, Skou showed that sodium ions and potassium ions bind with high affinity to different places in the enzyme. In addition, he showed that the phosphate group separated from ATP also binds to ATPase. He became Professor of Physiology at Aarhus in 1963 and Professor of Biophysics in 1977 as the success of the work brought Skou into contact with the wider academic community, attracting funding and students to his department over the following decades. He recalled: ‘Due to the work with the sodium–potassium pump, it became possible to attract clever young people, and the institute staff in a few years increased from 4 to 20–25 scientists. My research interest was concentrated around the structure and function of the active transport system, the Na+,K+-ATPase. A number of very excellent clever young scientists worked on different sides of the subject’. He officially retired in 1988 but kept an office at the university and continued to participate in research, publishing his last scientific article in the Journal of Psychiatric Research in 2015, when he was 96. A member of the Danish Academy of Sciences, Skou married his wife Ellen Margrethe Nielsen, a nurse, in 1948 and though their first daughter, born in 1950, died after 18 months, his daughters Hanne and Karen were born in 1952 and 1954. Skou died on 28 May 2018, survived by his wife, daughters, and grandchildren, and is remembered with the university’s Jens Christian Skou award, which is awarded annually to a promising junior researcher who has delivered excellent research within one or more of the Faculty of Health’s research areas. Professor Boyer was born 1918 in Provo, Utah and received his PhD in Biochemistry 1943 from the University of Wisconsin. From 1963 to 1989, he was Professor of Chemistry at Department of Chemistry and Biochemistry, University of California at Los Angeles (UCLA), and from 1965 to 1983 Director of the Molecular Biology Institute, UCLA. Dr Walker, now Professor Sir John Walker having been knighted in 1999 for his services to molecular biology, was born in 1941 in Halifax, Great Britain, received his MA and DPhil at Oxford University, and in 1982, became Senior Scientist at the Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge. He was founding Director of the MRC Mitochondrial Biology Unit from 1998 to 2012. He was elected to the Royal Society in 1995. Skou’s death came just four days before that of his fellow 1997 Laureate Boyer, who also died at the age of 99 years. Professor Mordecai Blaustein described Skou’s discovery of the Na+,K+-ATPase (NKA) as a ‘seminal advance’. In an area in which he has conducted important research, Prof Blaustein said that Skou’s ‘identification of the molecular basis for the active (energy-dependent) transport of Na+ and K+ against their respective electrochemical gradients’—for which he won the Nobel Prize—had left an immense legacy. Blaustein, a professor of physiology and medicine at the University of Maryland School of Medicine in Baltimore, noted that: ‘This transport is essential for cell volume stability (perhaps the primordial function), for the electrical excitability of neurons and muscle fibres, and many other aspects of cell signalling. Skou’s discovery was dogma-defying in that it provided the first evidence that an enzyme could also be an ion transporter. It set the stage for the discovery of numerous other ion transport ATPases. These include the Ca2+ ATPases of the endoplasmic/sarcoplasmic reticulum and the plasma membrane, the H+, K+ ATPases (molecular receptors for the widely used proton pump inhibitors such as omeprazole), and two types of Cu+ ATPases (mutations of which lead, respectively, to Wilson’s and Menkes’ diseases)’. It is an area that Prof Blaustein is continuing to investigate. While studying the NKA (in squid nerve fibres), he co-discovered another transporter, the Na+/Ca2+ exchanger (NCX). He recognized that this was the ‘missing link’ that explains how inhibition of the NKA by cardiotonic steroids increases the force of cardiac contraction (the basis of cardiotonic steroid use as heart failure therapy since 1785). He pointed out that Skou’s pivotal work facilitated the cloning of the NKA and its several subunits and functionally different isoforms—work which was followed by the discovery that the NKA is a hormone (endogenous ouabain, EO) receptor and that EO binding triggers diverse protein kinase signalling cascades in different cell types. Professor Blaustein said the discovery that NKA is functionally linked to the NCX led to the recognition that hormonal or drug (cardiotonic steroids, e.g. digoxin, digitoxin, ouabain) regulation of NKA also modulates Ca2+ transport and Ca2+ signalling in virtually all cell types. Ca2+ signalling is crucial for numerous cellular activities including cell division and cell death, as well as muscle contraction, secretion, and synaptic transmission. He said Skou’s work has helped shape clinical response and diagnosis, particularly in the cardiac arena, and notably in that ‘partial inhibition of the NKA by cardiotonic steroids leads to a net gain of Ca2+ via NCX,’—adding that ‘this underlies the aforementioned cardiotonic response’. He stressed, however, that while Skou’s discoveries were ground-breaking, it is an area where research is still very much ongoing. Nevertheless, he said the findings so far ‘reveal the enormous legacy of Skou’s seminal discovery’, and commented that ‘the full significance of NKA as a hormone receptor and signalling system is still far from complete and not widely appreciated’. It is a field that Professor Blaustein has played a key role in, suggesting in 1977 that a cardiotonic steroid-like substance (i.e. the natural ligand for the NKA ouabain binding site) plays a role in the pathogenesis of salt-dependent hypertension and 1981 (with colleagues), isolated and identified endogenous ouabain. They also showed that specific NKA isoforms and NCX co-localize in PM micro-domains in close proximity to junctional elements of the sarco-/endoplasmic reticulum, in functional units they call ‘PLasmERosomes’. The Na+ pump, on the right, is driven by ATP and extrudes three Na+ ions from the cytoplasm into the extracellular fluid (ECF) in exchange for two entering K+ (potassium) ions. This Na+ electrochemical gradient across the plasma membrane (PM) then drives the Na+/Ca2+ exchanger to extrude one Ca2+ in exchange for three Na+ ions that are recycled through the Na+ pump. When the Na+ pump is inhibited by EOor another cardiotonic steroid, the Na+ gradient is reduced so less Ca2+ is extruded and the Na+/Ca2+ exchanger may then even drive Ca2+ into the cytoplasm from the ECF. Conflict of interest: none declared.

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