FIGURE 14 Role of Ca2+ in synaptic transmission. (A) Experimental setup. (B1) In a Ca2+-free medium a depolarization of the presynaptic terminal does not lead to any transmitter release; (B2) when a small amount of Ca2+ is ejected just before a second depolarization, a postsynaptic potential is produced; (B3) if Ca2+ is ejected after the depolarization, no potential is produced. (Modified from Katz B, Miledi R. J Physiol 1967; 192:407-443.)

(increasing the concentration of Mg2+ in the extracellular medium also reduces transmitter release). An experiment that examines the role of Ca2+ in the release of chemical transmitter substances is illustrated in Fig. 14. Here the neuromuscular junction is used; one electrode is placed in the muscle cell to record the postsynaptic potential, and stimulating electrodes are placed close to the presynaptic terminal but not inside the terminal. The stimulating electrodes are sufficiently close to the presynaptic terminal to depolarize the terminal by extracellular means. A third electrode filled with CaCl2 is positioned near the presynaptic terminal. The preparation is perfused with a Ca2+-free medium. Figure 14B illustrates the results. In panel 1, stimulation of the presynaptic terminal produces no postsynaptic potential. Thus, in a Ca2+-free medium, transmitter release is abolished. In panel 2 (Fig. 14B), the presynaptic stimulation is preceded by a brief ejection of Ca2+ from the electrode containing CaCl2. Calcium ions are positively charged, so it is possible to eject a small amount of Ca2+ from the Ca2+ electrode simply by connecting the electrode to the positive pole of a battery. As a result of the brief ejection of Ca2+ prior to the stimulus, the depolarizing stimulus now produces a postsynaptic potential in the muscle cell. If Ca2+ is ejected after depolarization of the presynaptic terminal, no postsynaptic potential is produced in the muscle cell (panel 3, Fig. 14B). This experiment clearly indicates that Ca2+ is absolutely essential for the release of chemical transmitters. Furthermore, it illustrates that Ca2+ must be present just before (or during) depolarization of the presynaptic terminal. Based on these and other experiments, Katz and his colleagues proposed the Ca2+ hypothesis for chemical transmitter release.

Calcium ions are in high concentration outside the cell and in low concentration inside the cell. Furthermore, the inside of the cell is negatively charged with respect to the outside. As a result, there is a large chemical and electrical driving force for the influx of Ca2+. Normally, the cell is relatively impermeable to Ca2+, so even though there is a large driving force, Ca2+ does not enter the cell. It is proposed that there is a voltage-dependent change in Ca2+ permeability (Fig. 15A). Thus, depolarization of the presynaptic membrane results in an increase in Ca2+ permeability, and Ca2+ moves down its electrical and chemical gradient and flows into the synaptic terminal. The resultant elevation of intracellular Ca2+ concentration leads to the release of chemical transmitter (Fig. 15B).

Thus, according to this hypothesis, Ca2+ is the critical trigger for the release of chemical transmitter. One can artificially depolarize the presynaptic terminal to produce a voltage-dependent change in Ca2+ influx and release of transmitter. Normally, however, the

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