Title: A Theory for the Molecular Basis of Bioelectricity: the Work of David Nachmansohn Kresge N, Simoni RD, Hill RL Ref: Journal of Biological Chemistry, 280:152, 2005 : PubMed
David Nachmansohn (1899-1983) was born in Jekaterinoslav, Russia, but moved to Berlin at an early age.
He entered the University of Berlin in 1918 hoping to study the humanities, but with Germany's defeat in World War I and the social, political, and economic problems facing the newly established republic, he decided to pursue medicine instead. As his studies progressed, Nachmansohn became more interested in biology, and he eventually joined Peter Rona at the Charite (the university hospital of Berlin, University Medical School) for training in biochemistry when he graduated. Two years later he went to the Kaiser-Wilhelm Institut fur Biologie in Berlin-Dahlem to work with Otto Meyerhof.
At that time, Meyerhof was beginning studies on a newly discovered compound in muscle called phosphocreatine. The function of this compound was unknown,and Nachmansohn was given the task of looking for the relations between phosphocreatine breakdown, lactic acid formation, and muscle tension during isometric contraction in anaerobiosis. He discovered that rapidly contracting muscles contained more phosphocreatine than slowly contracting ones, which eventually led to the theory that phosphocreatine was involved in the regeneration of ATP that was broken down to provide energy in muscular contraction.
When Hitler came to power Nachmansohn left Germany. He was offered the opportunity to work at the Sorbonne and moved to Paris in 1933. While at the Sorbonne, Nachmansohn often attended the meetings of the British Physiological Society, held in London. One of the main topics of discussion at these meetings was the role of acetylcholine in nerve activity. Sir Henry Dale had proposed that acetylcholine transmits nerve impulses across junctions between neurons or nerve and muscle. It was also known that acetylcholine was rapidly hydrolyzed by acetylcholine esterase. Nachmansohn felt that more studies needed to be done on the nature, distribution, and concentration of acetylcholine esterase in tissues in order to determine its role in nerve activity. He began to work on this problem and soon discovered that acetylcholine esterase was present at high concentrations in many different types of excitable nerve and muscle fibers and in brain tissue but was hardly detectable in organs such as the liver or kidney. The concentration of acetylcholine esterase was also much higher at neuromuscular junctions than innerve fibers.
An article by J. Linhard describing the electric organs of fish as muscle fibers in which the muscular elements were either missing or present only in rudimentary form caught Nachmansohn's attention. He had seen a Torpedo fish at the 1937 Paris World's Fair and managed to procure some tissue for his studies. He discovered that the electric fish tissue contained exceedingly high concentrations of acetylcholine esterase. Later, in 1939, he and Egar Lederer purified acetylcholine esterase from the electric organ of the Torpedo fish. Then, in 1940, Nachmansohn, together with W. Feldberg and A. Fessard, provided the first unequivocal evidence for the electrogenic action of acetylcholine.
In 1940, Nachmansohn joined the faculty at Yale University and began studying the electric organ of the electric eel, which he obtained from the New York Aquarium. He found that not only did the organ contain high levels of acetylcholine esterase but that its phosphocreatine and ATP concentrations were comparable to those in striated muscle. He also discovered that the electrical discharge was accompanied by phosphocreatine breakdown. From this he hypothesized that the electric organ obtained the energy it required for the resynthesis of acetylcholine broken down during electric discharge by the same processes used to supply energy for muscular contraction: ATP and phosphocreatine breakdown and lactic acid formation.
Nachmansohn moved to New York in 1942 to become a faculty member at the College of Physicians and Surgeons at Columbia University. Soon after arriving he proved that electric tissue contains enzymes capable of utilizing the energy of ATP for the acetylation of choline by choline acetylase. This was the first time ATP had been shown to drive a synthetic reaction other than phosphorylation. Nachmansohn and A. L. Machado published this discovery in the Journal of Neurophysiology. Interestingly, three journals (Science, the JBC, and the Proceedings of the Society for Experimental Biology and Medicine) refused to publish this paper because the reviewers could not believe that ATP would participate in reactions other than phosphorylations. It was later found by Fritz Lipmann and others that acetylation requires acetyl-CoA and that ATP was needed for the synthesis of acetyl-CoA, which acetylates choline.
Meanwhile, work in a number of other laboratories confirmed that membranes of axons and conducting fibers, not just synaptic membranes, contained high concentrations of acetylcholine esterase. This led Nachmansohn to propose that acetylcholine acts as a signal that binds to a membrane-bound receptor and produces a conformational change. This increases local membrane permeability to ions and leads to depolarization and generation of an action potential. The acetylcholine is then rendered inactive by the esterase.
However, this hypothesis was based on the assumption that acetylcholineesterase was a specific enzyme that metabolized acetylcholine. In order for his theory to be true, Nachmansohn had to prove the enzyme's specificity and to establish its identity in the tissues he and others had used in their studies. The JBC Classic reprinted here contains these specificity and identity-proving experiments, done by Nachmansohn and Mortimer A. Rothenberg. They compared the abilities of acetylcholine esterases from a number of different tissues (used in previous experiments) to hydrolyze a variety of substrates. No matter what the tissue source, they found that no other substrate was split at a higher rate than acetylcholine, confirming that the enzyme was specific for acetylcholine.
Nachmansohn also proposed a theory for nerve conduction, postulating that a nerve impulse is generated through membrane depolarization by acetylcholine released by stimulus from an inactive complex with protein. The action potential causes the release of acetylcholine in adjacent sites leading to the propagation of the current along the nerve fiber. A rapid hydrolysis of acetylcholine by the esterase and the ion pump mechanism coupled to the breakdown of ATP restores the membrane potential. Nachmansohn presented this theory in 1959 in his book, Chemical and Molecular Basis of Nerve Activity. However, his ideas were not readily accepted by neurophysiologists. Today the current belief is that acetylcholine functions only as a synaptic transmitter that is released into the synaptic cleft. Axonal conduction, on the other hand, is believed to involve electric field effects on conformational transitions of protein-ion channels.
        
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Kresge N, Simoni RD, Hill RL (2005) A Theory for the Molecular Basis of Bioelectricity: the Work of David Nachmansohn Journal of Biological Chemistry280: 152-154
Kresge N, Simoni RD, Hill RL (2005) Journal of Biological Chemistry280: 152-154