A brief history of nerve action potentials after 1600

Action potentials of individual nerve axons are the electrical signals that propagate nervous information quickly around the brain and the body. This essay discusses milestones, from the definition of electricity in 1600 to the recent elucidation of the molecular structures of ion channels and membrane proteins that underlie action potential initiation and propagation. There were several key steps. The theory of electricity and electromagnetism had to be developed enough to allow discovery and measurement of animal electricity by biophysically minded physiologists. The theory of ions and electrochemistry had to be developed enough to allow prediction and verification of an ionic basis for animal electricity. Methods to amplify electrical signals with vacuum tubes and transistors were required for quantitative measurement and display of the action potentials and currents. Physiologists had to move from extracellular recording using nerve trunks to intracellular recording using single nerve fibers. Electronic feedback and mathematical modeling were needed to recognize the conductance changes of nerve membranes during activity. Pharmacology with neurotoxins allowed recognition of underlying voltage-gated ion channels. Protein purification, cloning, and sequencing identified the molecular basis of ion channels, and atomic structures showed in graphic detail how they work. Significance Statement: This is a brief scientific history of the action potential, the quintessential electrical message of our nerves. As with other histories in biology, this one reiterates that major scientific advances depend on advances in physics and physical chemistry, development of the right preparations and instruments, and the experimental genius and conceptual insights of clever scientists and their students. (c) 2024 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.