Our ability to do gymnastics, to perceive a colorful world, of nerve are needed to bring the next region into activity. and to process language relies on rapid communication This meant that depolarization is the natural stimulus among neurons. Such signaling, the fastest in our bodfor action potential propagation. JZ Young (1936) reies, involves electrical messages produced as ion chandiscovered the giant axon of the squid. It provided the nels in cell membranes open and close. Various ion first convenient way to place electrodes and even elecchannels mediate sensory transduction, electrical “comtrode arrays inside an excitable cell. Cole and Curtis putations,” propagation over long distances, and synap-(1939) showed that the membrane of the squid giant tic transmission. Here, we focus on voltage-gated ion axon increases its conductance 40-fold during an action channels, the family of channels that includes the famil- potential, in apparent agreement with Bernstein’s earlier iar Na+, K+, and Ca2+ channels of nerve and muscle theory of membrane breakdown. Hodgkin and Huxley excitability. In the computer metaphor of the brain, the(1939) discovered with intracellular electrodes that the voltage-gated ion channels are like the transistors of peak of theaction potentialovershoots 0mV by a signifilogical circuits, detecting, amplifying, and reshaping cant margin. The overshoot was a serious problem for electrical messages. Our basic understanding of these the Bernstein theory, and Hodgkin and Katz (1949) evenproteins maintains the framework and rigor established tually provided the crucial resolution: the overshoot is 50 years ago by Hodgkin and Huxley (1952), enriched by determined by the Na+ equilibrium potential and must much new molecular information and by insights gained be due to Na+ entry during the action potential. from patch-clamp methods. With this background, Hodgkin and Huxley sought to Although we have had full amino acid sequences of understand how excitation regulates the entry of Na+ voltage-gated channels for over a decade, we still lack ions. They developed the voltage clamp to measure even modest resolution three-dimensional information. ion movements as electric currents. The clamp records All three-dimensional diagrams in the literature derive revealed an inward current followed by an outward current during step depolarizations. In a major conceptual from functional studies without the benefit of crystallogleap, Hodgkin and Huxley (1952) deduced that these raphy or NMR. Figure 1A represents widely accepted membrane currents could be assigned to Na+ and K+ functional information, much of it deriving from early permeability mechanisms whose conductances are biophysical and pharmacological work that will be defunctions of time and membrane potential. The assumpscribed in this article. An overriding conclusion is that tion of separable permeability components and the realion channels are aqueous pores. Proceeding through ization that membrane potential is the controlling varithe pore from the outside, an ion would find a wide outer able were the paradigm shifts that opened a new field vestibule, a narrow selectivity filter, a voluminous inner of inquiry. Their five seminal papers systematically exvestibule, and finally, at the cytoplasmic end, the gating tracted kinetic constants for an empirical description of machinery that closes the pore. Highly charged voltage the conductance changes, showed that this detailed sensors control activation of the channel but are less kinetic description—the Hodgkin-Huxley model—sufimportant for inactivation. All of the voltage-gated chanfices to explain all of the classical …