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FIGURE 6 Changes in the amplitude of the action potential in the squid giant axon as a function of the extracellular concentration of Na+ reduced to 70% (A), 50% (B), and 33% (C) of its normal value. (Modified from Hodgkin AL, Katz B. J Physiol 1949; 108:37.)

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FIGURE 6 Changes in the amplitude of the action potential in the squid giant axon as a function of the extracellular concentration of Na+ reduced to 70% (A), 50% (B), and 33% (C) of its normal value. (Modified from Hodgkin AL, Katz B. J Physiol 1949; 108:37.)

Overton, like Bernstein, could not test his hypothesis experimentally because microelectrodes were not available. Just as Hodgkin and his colleagues critically tested Bernstein's hypothesis for the resting potential, they also examined and extended Overton's observations. One of the earlier experiments performed by Hodgkin and Katz is illustrated in Fig. 6.

Hodgkin and Katz repeatedly initiated action potentials in the squid giant axon while they artificially altered the extracellular Na+ concentration. When the extracellular Na+ concentration was reduced to 70% of its normal value (Fig. 6A), there was a slight reduction in the amplitude of the action potential. Reducing the Na+ concentration to 50% and 33% of its normal value produced further reductions in the amplitude of the action potential. These experiments, therefore, directly confirmed Overton's initial observations that Na+ is essential for the initiation of action potentials. (Exceptions to this are action potentials in cardiac and smooth muscle cells; see Chapters 8 and 11.)

Hodgkin and his colleagues took these observations one step further. They suggested that, during an action potential, the membrane behaved as though it was becoming selectively permeable to Na+. In a sense, the membrane was switching from its state of being highly permeable to K+ at rest to being highly permeable to Na+ at the peak of the action potential. If a membrane is highly permeable to Na+ at the peak of the action potential (for the sake of simplicity we assume that the membrane is solely permeable to Na+ and no other ions), what potential difference would one predict across the cell membrane? If the membrane is only permeable to Na+, the membrane potential should equal the Na+ equilibrium potential (ENa), and

Indeed, when the known values of extracellular and intracellular Na+ concentrations for the squid giant axon are substituted, a value of +55 mV is calculated. This is approximately the peak amplitude of the action potential. Is this simply a coincidence? It is possible that the membrane is permeable to other ions as well. Perhaps the action potential is due to an increase in Ca2+ permeability; Ca2+ is in high concentration outside and low concentration inside the cell, so part of the action potential might be due to a selective increase in Ca2+ permeability. How can this issue be resolved? If the peak amplitude of the action potential is determined by ENa, one would expect that as the extracellular levels of Na+ are altered, the peak amplitude of the action potential would change according to the Nernst equation. Furthermore, because of the logarithmic relationship in the Nernst equation, if the extracellular Na+ concentration is changed by a factor of 10, the Na+ equilibrium potential and the peak amplitude of the action potential should change by a factor of 60 mV.

Figure 7 illustrates a test of this hypothesis. The peak amplitude of the action potential, shown on the vertical axis, is measured as a function of the extracellular Na+ concentration. The dots on the graph represent the peak amplitude of the action potential recorded at various extracellular concentrations of Na+. The straight line is the relationship that describes the Na+ equilibrium potential as a function of extracellular Na+.

Although there are some deviations between the predicted Na+ equilibrium potential and the peak amplitude of the action potential (the action potential never quite reaches the value of the Na+ equilibrium potential), the critical observation is that the slopes of these two lines are nearly identical. For a tenfold change in the extracellular Na+ concentration, there is approximately a 60-mV change in the peak amplitude of the action potential. These experiments, therefore, provide strong experimental support for the hypothesis that

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