A Theory for the Molecular Basis of Bioelectricity: the Work of DavidNachmansohn
Year: 2005
Type: article
Abstract: Studies on Cholinesterase. I. On the Specificity of the Enzyme in NerveTissue (Nachmansohn, D., and Rothenberg, M. A. (1945) J. Biol. Chem.158, 653-666) David Nachmansohn (1899-1983) was born in Jekaterinoslav, Russia, but movedto Berlin at an earlyage. 1All biographical information on David Nachmansohn was taken from Ref.3Ochoa S. Biographical Memoir ofDavid Nachmansohn. 58. National Academy of Sciences, Washington, D.C.1989: 356-405Google Scholar. 1All biographical information on David Nachmansohn was taken from Ref.3Ochoa S. Biographical Memoir ofDavid Nachmansohn. 58. National Academy of Sciences, Washington, D.C.1989: 356-405Google Scholar. He entered theUniversity of Berlin in 1918 hoping to study the humanities, but withGermany's defeat in World War I and the social, political, and economicproblems facing the newly established republic, he decided to pursue medicineinstead. As his studies progressed, Nachmansohn became more interested inbiology, and he eventually joined Peter Rona at the Charité (theuniversity hospital of Berlin University Medical School) for training inbiochemistry when he graduated. Two years later he went to the Kaiser-WilhelmInstitut für Biologie in Berlin-Dahlem to work with Otto Meyerhof, whowas featured in a previous Journal of Biological Chemistry (JBC) Classic (www.jbc.org). At that time, Meyerhof was beginning studies on a newly discovered compoundin muscle called phosphocreatine. The function of this compound was unknown,and Nachmansohn was given the task of looking for the relations betweenphosphocreatine breakdown, lactic acid formation, and muscle tension duringisometric contraction in anaerobiosis. He discovered that rapidly contractingmuscles contained more phosphocreatine than slowly contracting ones, whicheventually led to the theory that phosphocreatine was involved in theregeneration of ATP that was broken down to provide energy in muscularcontraction. When Hitler came to power Nachmansohn left Germany. He was offered theopportunity to work at the Sorbonne and moved to Paris in 1933. While at theSorbonne, Nachmansohn often attended the meetings of the British PhysiologicalSociety, held in London. One of the main topics of discussion at thesemeetings was the role of acetylcholine in nerve activity. Sir Henry Dale hadproposed that acetylcholine transmits nerve impulses across junctions betweenneurons or nerve and muscle. It was also known that acetylcholine was rapidlyhydrolyzed by acetylcholine esterase. Nachmansohn felt that more studiesneeded to be done on the nature, distribution, and concentration ofacetylcholine esterase in tissues in order to determine its role in nerveactivity. He began to work on this problem and soon discovered thatacetylcholine esterase was present at high concentrations in many differenttypes of excitable nerve and muscle fibers and in brain tissue but was hardlydetectable in organs such as the liver or kidney. The concentration ofacetylcholine esterase was also much higher at neuromuscular junctions than innerve fibers. An article by J. Linhard describing the electric organs of fish as musclefibers in which the muscular elements were either missing or present only inrudimentary form caught Nachmansohn's attention. He had seen aTorpedo fish at the 1937 Paris World's Fair and managed to procuresome tissue for his studies. He discovered that the electric fish tissuecontained exceedingly high concentrations of acetylcholine esterase. Later, in1939, he and Egar Lederer purified acetylcholine esterase from the electricorgan of the Torpedo fish. Then, in 1940, Nachmansohn, together withW. Feldberg and A. Fessard, provided the first unequivocal evidence for theelectrogenic action of acetylcholine. In 1940, Nachmansohn joined the faculty at Yale University and beganstudying the electric organ of the electric eel, which he obtained from theNew York Aquarium. He found that not only did the organ contain high levels ofacetylcholine esterase but that its phosphocreatine and ATP concentrationswere comparable to those in striated muscle. He also discovered that theelectrical discharge was accompanied by phosphocreatine breakdown. From thishe hypothesized that the electric organ obtained the energy it required forthe resynthesis of acetylcholine broken down during electric discharge by thesame processes used to supply energy for muscular contraction: ATP andphosphocreatine breakdown and lactic acid formation. Nachmansohn moved to New York in 1942 to become a faculty member at theCollege of Physicians and Surgeons at Columbia University. Soon after arrivinghe proved that electric tissue contains enzymes capable of utilizing theenergy of ATP for the acetylation of choline by choline acetylase. This wasthe first time ATP had been shown to drive a synthetic reaction other thanphosphorylation. Nachmansohn and A. L. Machado published this discovery in theJournal of Neurophysiology(1Nachmansohn D. Machado A.L. Theformation of acetylcholine. A new enzyme choline acetylase..J.Neurophysiol. 1943; 6: 397-403Crossref Google Scholar). Interestingly, threejournals (Science, the JBC, and the Proceedings of theSociety for Experimental Biology and Medicine) refused to publish thispaper because the reviewers could not believe that ATP would participate inreactions other than phosphorylations. It was later found by Fritz Lipmann andothers that acetylation requires acetyl-CoA and that ATP was needed for thesynthesis of acetyl-CoA, which acetylates choline. Meanwhile, work in a number of other laboratories confirmed that membranesof axons and conducting fibers, not just synaptic membranes, contained highconcentrations of acetylcholine esterase. This led Nachmansohn to propose thatacetylcholine acts as a signal that binds to a membrane-bound receptor andproduces a conformational change. This increases local membrane permeabilityto ions and leads to depolarization and generation of an action potential. Theacetylcholine 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 forhis theory to be true, Nachmansohn had to prove the enzyme's specificity andto establish its identity in the tissues he and others had used in theirstudies. The JBC Classic reprinted here contains these specificity andidentity-proving experiments, done by Nachmansohn and Mortimer A. Rothenberg.They compared the abilities of acetylcholine esterases from a number ofdifferent tissues (used in previous experiments) to hydrolyze a variety ofsubstrates. No matter what the tissue source, they found that no othersubstrate was split at a higher rate than acetylcholine, confirming that theenzyme was specific for acetylcholine. Nachmansohn also proposed a theory for nerve conduction, postulating that anerve impulse is generated through membrane depolarization by acetylcholinereleased by stimulus from an inactive complex with protein. The actionpotential causes the release of acetylcholine in adjacent sites leading to thepropagation of the current along the nerve fiber. A rapid hydrolysis ofacetylcholine by the esterase and the ion pump mechanism coupled to thebreakdown of ATP restores the membrane potential. Nachmansohn presented thistheory in 1959 in his book, Chemical and Molecular Basis of NerveActivity (2Nachmansohn D. Chemical andMolecular Basis of Nerve Activity. Academic Press, NewYork1959Google Scholar). However, his ideas were not readily accepted by neurophysiologists. Todaythe current belief is that acetylcholine functions only as a synaptictransmitter that is released into the synaptic cleft. Axonal conduction, onthe other hand, is believed to involve electric field effects onconformational transitions of protein-ion channels.
Source: Journal of Biological Chemistry
Language: English
Subfield: History and Philosophy of Science
Field: Arts and Humanities
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1502559297