The transmission of information within a single neuron is an electrical process and depends on the semipermeable nature of the cell membrane. When the normal resting electrical charge of a neuron is disturbed sufficiently by incoming signals from other cells, a threshold is reached that initiates the electrical signal (action potential) that conveys the message along the entire length of the axon to the axon terminals. This section of the post looks at each of the stages: resting membrane potential, local potentials, threshold, and action potential.
Ion distribution is responsible for the cell’s resting potential
All neurons have a difference in electrical charge inside the cell compared to outside the cell, called the resting membrane potential. It can be measured by placing an electrode on the exterior of the cell in the extracellular fluid and a second, much finer microelectrode into the intracellular fluid inside the cell (Figure 2.9A and B). The inside of the neuron is more negative than the outside, and a voltmeter would tell us that the difference is approximately -70 millivolts (mV), making the neuron polarized in its resting state.
The selective permeability of the membrane and uneven distribution of ions inside and outside the cell is responsible for the „ membrane potential. This means that when the cell is at rest, there are more negatively charged particles (ions) inside the cell and more positively charged ions outside the cell. Figure 2.10 shows the relative concentration of different ions on either side of the mem, , brane. Inside we find many large, negatively charged molecules, such as proteins and amino acids, that’cannot leave the cell. Potassium is also in much higher concentration (perhaps 20 times higher) inside than out. In contrast, Na+ and Cl- are in greater concentration outside the cell than inside.
Several forces are responsible for this ion distribution and membrane potential. The concentration gradient and electrostatic pressure for the K+ ion is particularly important, because K+ moves more freely through the membrane than other ions since some of its channels are not gated at the resting potential. Recall that ions move through relatively specific channels and that most are gated, meaning that they are normally held closed until opened by a stimulus. Since the inside of the cell normally has numerous large, negatively charged materials that do not move through the membrane, the positively charged K+ ion is pulled into the cell because it is attracted to the internal negative charge (electrostatic pressure). However, as the concentration of K+ inside rises, K+ responds to the concentration gradient by moving out of the cell. The concentration gradient is a force to equalize the amount or concentration of material across a biological barrier. When the two forces on K+ (inward electrostatic force and outward concentration gradient) are balanced (called the equilibrium potential for potassium), the membrane potential is still more negative inside (-70 mV). In addition, because small amounts of Na+ leak into the cell, an energy-dependent pump (the Na+-K+ pump) contributes to the resting potential by exchanging Na+ for K+ across the membrane. For every three ions of Na+ pumped out, two K+ ions are pumped in, keeping the inside of the cell negative.
In summary, all cells are polarized at rest, having a difference in charge across their membranes. The potential is due to the uneven distribution of ions across the membrane that occurs because ions move through relatively specific channels that are normally not open. K+ has greater ability to move freely through ungated channels. Although all cells are polarized, what makes neurons different is that rapid changes in the membrane potential provide the means for neurons to conduct information, which in turn influences hundreds of other cells in the nervous system. This rapid change in membrane potential that is propagated down the length of the axon is called the action potential. In order for a cell to generate an action potential, the membrane potential must be changed from resting (-70 mV) to the threshold for firing (-50 mV). At -50 mV, voltage-gated Na+ channels open, generating a rapid change in membrane potential. Before we look closely at the action potential, let s see what happens to a neuron to cause the membrane potential to change from resting to threshold.
Local potentials are small, transient changes in membrane potential
While the membrane potential at rest is -70 mV, various types of stimuli that disturb the membrane can open ion channels momentarily, causing small, local changes in ion distribution and hence electrical potential differences called local potentials. To visualize the small changes in membrane potential, we attach our electrodes to an amplifier and to a computer that measures and records the changing voltage over time (Figure 2.11A and B). For instance, applying a small, positive electrical current or momentarily opening gated Na+ channels allows a relatively small number of Na+ ions to enter the cell. The ions enter because Na+ is more concentrated outside than inside, so the concentration gradient drives the ions in. The oscilloscope shows that the positively charged ions make the inside of the cell slightly more positive in a small, localized area of the membrane, bringing the membrane potential a tiny bit closer to the threshold for firing. This change is called a local depolarization and is excitatory. Other stimuli may open CL channels, which allow Cl- into the cell because the ion’s concentration is greater on the outside of the cell. The local increase in the negatively charged ion makes the cell slightly more negative inside and brings the resting potential farther away from threshold. This hyperpolarization of the membrane is inhibitory. Finally, if gated K+ channels are opened by a stimulus, K+ is driven outward locally based on its concentration gradient. Because positively charged ions leave the cell, it becomes just slightly more negative inside, making the membrane potential farther from threshold and causing a local hyperpolarization. These local potentials are of significance to psychopharmacology because when drugs or neurotransmitters bind to particular receptors in the nervous system, they may momentarily open specific ion channels, causing an excitatory or inhibitory effect. Since neurotransmitters act on the postsynaptic membrane, the effects are called excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs).
These local potentials (hyperpolarizations and depolarizations), generated on the dendrites and cell body, have several significant characteristics. First, they are graded, meaning that the larger the stimulus, the greater the magnitude of the hyper- or depolarization. As soon as the stimulus stops, the ion channels close and the membrane potential returns to resting levels. These local potentials also decay rapidly as they passively travel along the cell membrane. Finally, local potentials show summation, sometimes called integration, meaning that several small depolarizations can add up to larger changes in membrane potential, as several hyperpolarizations can produce larger inhibitory changes. When hyperpolarizations and depolarizations occur at the same time, they cancel each other out. The receptor areas of a neuron involved in local potential generation receive information from thousands of synaptic connections from other neurons that at any given instant produce IPSPs or EPSP. The integration of EPSPs and IPSPs occurs in the axon hillock and is responsible for the generation of the action potential if the threshold for activation is reached.
Sufficient depolarization at the axon hillock opens voltage-gated Na+ channels, producing an action potential
The summation of local potentials at the axon hillock is responsible for the generation of the action potential. The -50mV membrane potential (threshold) is responsible for opening large numbers of Na+ channels that are voltage gated; that is, the change in voltage across the membrane near these channels is responsible for opening them (Figure 2.13). Since Na+ is much more concentrated outside the cell, its concentration gradient moves it inward; in addition, since the cell at threshold is still negative inside, Na+ is also driven in by the electrostatic gradient. These two forces move large numbers of Na+ ions into the cell very quickly, causing the rapid change in membrane potential from -50 mV to +40 mV (called the rising phase of the action potential) before the Na+ channels close and remain closed for a fixed period of time while they reset. The time during which the Na+ channels are closed and cannot be opened, regardless of the amount of excitation, prevents the occurrence of another action potential and is called the absolute refractory period. The closing of Na+ channels explains why the maximum number of action potentials that can occur is about 1200 impulses per second. The action potential is a rapid change in membrane potential lasting only about 1 millisecond. When the membrane potential approaches resting levels, the Na+ channels are reset and ready to open.
Meanwhile, during the rising phase, the changing membrane potential due to Na+ entry causes voltage-gated K+ channels to open, and K+ moves out of the cell. K+ channels remain open after Na+ channels have closed, causing the membrane potential to return to resting levels. The membrane potential actually overshoots the resting potential, so the membrane remains hyperpolarized for a short amount of time until the excess K+ diffuses away or is exchanged for Na+ by the Na+-K+ pump. Because the membrane is more polarized than normal, it is more difficult to generate an action potential. The brief hyperpolarizing phase is call the relative refractory period because it takes more excitation to first reach resting potential and further depolarization to reach threshold. The relative refractory period explains why the intensity of stimulation determines rate of firing. Low levels of excitation cannot overcome the relative refractory period, but with an increasing amount of excitation, the neuron will fire again as soon as the absolute refractory period has ended.
If the threshold is reached, an action potential occurs (first at the hillock). Its size is unrelated to the amount of stimulation; hence it is considered all-or-none. Reaching the threshold will generate the action potential, but more excitatory events (EPSPs) will not make it larger; fewer excitatory events will not generate an action potential at all. The action potential moves along the axon because the positively charged Na+ ions spread passively to nearby regions of the axon, which by changing the membrane potential to thresh-old causes the opening of other voltage-gated Na+ channels. The regeneration process of the axon potential continues sequentially along the entire axon and does not decrease in size; hence it is called nondecremental (i.e., it does not decay). In myelinated axons the speed of conduction is as much as 15 times quicker than in nonmyelinated axons because the regeneration of the action potential occurs only at the nodes of Ranvier. This characteristic makes the conduction seem to jump along the axon, so it is called saltatory conduction. In addition, myelinated axons use less energy because the Na+-K+ pump, which uses large amounts of ATP, only has to work at the nodes rather than all along the axon.
Drugs and poisons alter axon conduction
As we will learn, most drugs act at synapses to modify chemical transmission. However, a few alter action potential conductance along the axon. Drugs that act as local anesthetics, such as procaine (Novocaine), lidocaine (Xylocaine), and benzocaine (Anesthesin), all impair axonal conduction by blocking voltage-gated Na+ channels. It should be apparent that if voltage-gated Na+ channels cannot open, then an action potential cannot occur and transmission of the pain signal cannot reach the brain. Hence the individual is not aware of the damaging stimulus. Local anesthetics are injected into specific sites between the tissue damage and the CNS to prevent conduction, but saxitoxin is a poison that blocks voltage-gated Na+ channels throughout the nervous system because it is ingested. (Saxotoxin is found in shellfish exposed to the “red tide” [caused by the organism Gonyaulax]). Oral ingestion circulates the toxin throughout the body and causes conduction failure and subsequent death due to suffocation.
All cells are polarized at rest, meaning that they have a difference in the electrical charge across the cell membrane. For neurons, the difference is usually about -70 mV, with the inside being more negative than the outside. The action potential is an electrical event that is generated at the axon hillock and conducted down the full length of the axon to the terminals. The action potential can occur only if small, local electrical potentials, occurring on the soma and dendrites of the cell, summate and change the resting potential (-70 mV) to the threshold for firing (-50 mV).
The resting membrane potential exists because the semi- permeable membrane causes ions to be unevenly distributed on each side of the membrane. In particular, because large, negatively charged molecules are trapped inside the cell, K+ ions are forced into the neuron through nongated channels by electrostatic pressure. As the internal concentration of K+ ions increases, the concentration gradient for K+ pushes the ions out of the cell. At the point when the inward pressure and outward pressure are balanced (equilibrium potential), the cell is still negative inside, with a -70-mV difference. Because there is some leakage of Na+ into the cell, the Na+-K+ pump also helps to maintain the negative membrane potential by exchanging three Na+ ions (moved out of the cell) for two K+ ions (taken in).
Local potentials are small, short-lived changes in membrane potential following the opening of ligand-gated channels. These channels are found largely on the soma and dendrites and are opened when a neurotransmitter or drug binds to the receptor associated with the channel. Opening ligand-gated Na+ channels allows a relatively small amount of Na+ to enter the cell, making it slightly more positive in the local area near the channels. When the cell is more positive inside, the cell membrane potential is closer to the threshold for firing, so it is called an excitatory postsynaptic potential (EPSP). Other ligands may open Cl- channels, allowing Cl- to enter on its concentration gradient and making the cell more negative. Increased negative charge inside the cell moves the membrane potential farther from the threshold; hence it causes inhibitory postsynaptic potentials (IPSPs). The third type of channel involved in creating local potentials is the ligand-gated K+ channel. When it is opened, K+ exits according to its concentration gradient, leaving the cell more negative inside and farther from the threshold (IPSP).
The summation of all the EPSPs and IPSPs occurring at any single moment in time occurs at the axon hillock. If the threshold (-50 mV) is reached, the great number of voltage- gated Na+ channels found in that region suddenly open, allowing large amounts of Na+ to enter the cell to produce the massive depolarization known as the action potential. When the inside of the cell becomes positive (+40 mV), voltage-gated Na+ channels close and cannot be opened until they reset at the resting potential. During the time when the channels are closed, called the absolute refractory period, no action potential can occur.
In addition, as the cell becomes more positive inside, voltage-gated K+ channels open and K+ exits from the cell, bringing the membrane potential back toward resting levels. The overshoot typically seen is a state in which the cell is more polarized than normal, so it is more difficult to reach the threshold to generate another action potential.
Once the action potential is generated at the axon hillock in an all-or-none fashion, it moves down the length of the axon by sequential opening of voltage-gated Na+ channels. In myelinated axons, the regeneration of the action potential occurs only at the nodes of Ranvier, producing a rapid, saltatory conduction that is also more energy efficient because the Na+-K+ pump needs to exchange ions only at the nodes. Regardless of the extent of myelination, all action potentials are nondecremental.