Roles of Other Ions During the Action Potential
Thus far, we have considered only the roles of sodium and potassium ions in the generation of the action potential. At least two other types of ions must be con-sidered: negative anions and calcium ions.
Impermeant Negatively Charged Ions (Anions) Inside the Nerve Axon. Inside the axon are many negatively charged ionsthat cannot go through the membrane channels. They include the anions of protein molecules and of many organic phosphate compounds, sulfate compounds, and so forth. Because these ions cannot leave the interior of the axon, any deficit of positive ions inside the mem-brane leaves an excess of these impermeant negative anions. Therefore, these impermeant negative ions are responsible for the negative charge inside the fiber when there is a net deficit of positively charged potas-sium ions and other positive ions.
Calcium Ions. The membranes of almost all cells of thebody have a calcium pump similar to the sodium pump, and calcium serves along with (or instead of) sodium in some cells to cause most of the action potential. Like the sodium pump, the calcium pump pumps calcium ions from the interior to the exterior of the cell mem-brane (or into the endoplasmic reticulum of the cell), creating a calcium ion gradient of about 10,000-fold. This leaves an internal cell concentration of calcium ions of about 10–7 molar, in contrast to an external con-centration of about 10–3 molar.
In addition, there are voltage-gated calcium channels. These channels are slightly permeable to sodium ions as well as to calcium ions; when they open, both calcium and sodium ions flow to the interior of the fiber. There-fore, these channels are also called Ca++-Na+channels. The calcium channels are slow to become activated, requiring 10 to 20 times as long for activation as the sodium channels. Therefore, they are called slow chan-nels, in contrast to the sodium channels, which are called fast channels.
Calcium channels are numerous in both cardiac muscle and smooth muscle. In fact, in some types of smooth muscle, the fast sodium channels are hardly present, so that the action potentials are caused almost entirely by activation of slow calcium channels.
Increased Permeability of the Sodium Channels When There Is a Deficit of Calcium Ions. The concentration ofcalcium ions in the extracellular fluid also has a pro-found effect on the voltage level at which the sodium channels become activated. When there is a deficit of calcium ions, the sodium channels become activated (opened) by very little increase of the membrane poten-tial from its normal, very negative level. Therefore, the nerve fiber becomes highly excitable, sometimes dis-charging repetitively without provocation rather than remaining in the resting state. In fact, the calcium ion concentration needs to fall only 50 per cent below normal before spontaneous discharge occurs in some peripheral nerves, often causing muscle “tetany.” This is sometimes lethal because of tetanic contraction of the respiratory muscles.
The probable way in which calcium ions affect the sodium channels is as follows: These ions appear to bind to the exterior surfaces of the sodium channel protein molecule. The positive charges of these calcium ions in turn alter the electrical state of the channel protein itself, in this way altering the voltage level required to open the sodium gate.
Up to this point, we have explained the changing sodium and potassium permeability of the membrane, as well as the development of the action potential itself, but we have not explained what initiates the action potential. The answer is quite simple.
A Positive-Feedback Vicious Cycle Opens the Sodium Channels.
First, as long as the membrane of the nerve fiber remains undisturbed, no action potential occurs in the normal nerve. However, if any event causes enough initial rise in the membrane potential from –90 milli-volts toward the zero level, the rising voltage itself causes many voltage-gated sodium channels to begin opening. This allows rapid inflow of sodium ions, which causes a further rise in the membrane potential, thus opening still more voltage-gated sodium channels and allowing more streaming of sodium ions to the interior of the fiber. This process is a positive-feedback vicious cycle that, once the feedback is strong enough, contin-ues until all the voltage-gated sodium channels have become activated (opened). Then, within another frac-tion of a millisecond, the rising membrane potential causes closure of the sodium channels as well as opening of potassium channels, and the action poten-tial soon terminates.
Threshold for Initiation of the Action Potential. An actionpotential will not occur until the initial rise in mem-brane potential is great enough to create the vicious cycle described in the preceding paragraph. This occurs when the number of Na+ ions entering the fiber becomes greater than the number of K+ions leaving the fiber. A sudden rise in membrane potential of 15 to 30 millivolts usually is required. Therefore, a sudden increase in the membrane potential in a large nerve fiber from –90 millivolts up to about –65 millivolts usually causes the explosive development of an action potential. This level of –65 millivolts is said to be the threshold for stimulation.