An action potential represents a fundamental process in excitable cells, characterized by a rapid and transient change in the electrical potential across the cell membrane. This electrical signal is crucial for communication in the nervous system, muscle contraction, and hormone secretion. The action potential is an “all-or-nothing” event, meaning that it either occurs fully or not at all, and its amplitude is independent of the stimulus strength.
Action Potential at the Cellular Level
While action potentials are most famously associated with neurons, they are also observed in other excitable cells like cardiac muscle cells and certain endocrine cells. Within a neuronal population, the electrical properties of individual cells, such as the resting membrane potential, maximum firing rate, and action potential duration, can vary considerably. These differences are primarily determined by the types, number, distribution, and kinetics of ion channels present in the cell membrane.
In the heart, specialized pacemaker cells located in the sinoatrial (SA) node spontaneously generate action potentials. In contrast to neurons, calcium ions play a crucial role in the action potentials of pacemaker cells. The influx of calcium ions through T-type calcium channels gradually depolarizes the cell until it reaches the threshold for L-type voltage-gated calcium channels, triggering an action potential. This electrical signal then spreads throughout the heart via myocardiocytes, which are cardiac muscle cells that contract and conduct the electrical impulse to neighboring cells. Myocardiocytes, unlike pacemaker cells but similar to neurons, use voltage-gated sodium channels for rapid depolarization during action potential initiation.
Development of Action Potentials
The properties of action potentials change during development due to various factors, including alterations in ion concentrations, ion channel density, and ion channel localization. Myelination, the process of wrapping axons with a fatty sheath called myelin, also significantly affects action potential propagation speed.
During embryonic development, the intracellular concentration of sodium ions decreases significantly. Since the relative concentrations of ions inside and outside the cell determine the driving force for ion movement across the membrane, changes in ion concentration can dramatically affect action potential dynamics. The decrease in intracellular sodium concentration during neuronal maturation leads to higher peak voltages during action potentials.
Early in development, action potentials are typically slow and prolonged. However, as development proceeds, there is an increase in the expression of sodium channels, resulting in a more rapid depolarization phase. Simultaneously, an increase in potassium channel expression leads to a shorter action potential duration. Shorter action potentials allow cells to fire at higher frequencies, enabling faster information processing. Moreover, the precise localization of voltage-gated ion channels is essential for efficient action potential propagation. In myelinated axons, voltage-gated channels are clustered at high density at the nodes of Ranvier, which are gaps in the myelin sheath. This clustering lowers the threshold for action potential initiation. Similarly, in unmyelinated axons, voltage-gated sodium channels are often clustered into lipid raft microdomains. This clustering optimizes action potential conduction and fidelity by minimizing the number of channels required for propagation and increasing the conduction speed, compared to a diffuse distribution of channels.
The Function of Action Potentials
A typical neuronal action potential consists of three distinct phases: depolarization, repolarization, and hyperpolarization. The initial depolarization phase is triggered when the membrane potential reaches a threshold voltage, causing voltage-gated sodium channels (Nav) to open and allow an influx of sodium ions. This influx of positive charge further depolarizes the membrane, leading to the opening of more Nav channels in a positive feedback loop. Depolarization lasts for approximately 1 millisecond in mature neurons, after which the Nav channels become inactivated and unable to conduct ions.
Repolarization begins when voltage-gated potassium channels (Kv) open. Although Kv channels have a similar threshold voltage to Nav channels, their activation kinetics are much slower. After approximately 1 millisecond, the slower Kv channels begin to open, coinciding with the inactivation of the faster Nav channels. The outflow of potassium ions from the cell causes a decrease in membrane potential toward the cell’s resting voltage. As the membrane potential falls below the threshold, both Nav and Kv channels begin to close. However, the Kv channels have slow kinetics and remain open slightly longer than necessary to restore the cell to its resting membrane voltage. This brief dip in membrane potential below the normal resting voltage is called hyperpolarization.
Action potentials propagate signals along the length of an axon differently in myelinated and unmyelinated axons. Myelin acts as an insulator, preventing ion flow across the membrane. The myelin sheath is interrupted at regularly spaced intervals called the nodes of Ranvier. Depolarizing current from an action potential travels rapidly through the cytoplasm of the axon, insulated by myelin, until it reaches the next node of Ranvier. At each node, the membrane depolarizes above the threshold voltage, and the influx of sodium ions initiates another action potential through Nav channels. This node-to-node propagation, known as saltatory conduction, significantly increases the conduction velocity compared to unmyelinated axons.
In unmyelinated axons, depolarization of the cell membrane must spread to the immediately adjacent region of the membrane, passively raising the potential until it reaches the threshold voltage. Thus, the action potential propagates as a continuous wave of depolarization.
The initiation of a neuronal action potential usually occurs at the axon hillock, the region where the axon originates from the cell body. However, in sensory neurons, the action potential is initiated at the distal terminal of the axon and propagates toward the central nervous system. These spike initiation zones have a high density of Nav channels, which reduces input resistance and lowers the amount of excitation required to trigger an action potential.
Mechanism Behind Action Potential
Voltage-gated ion channels are composed of four domains surrounding a central pore, with each domain containing six transmembrane alpha-helices. Within each domain, the fourth alpha-helix (S4) contains positively charged lysine and/or arginine amino acids. When the cell depolarizes, the positive residues within S4 are repelled, causing a conformational change that opens the channel pore. Sodium channels undergo rapid inactivation. After the channel pore opens, the linker region between domains III and IV binds to residues within the pore, blocking the flow of ions. Although the channel remains technically “open” when the cell is above the threshold voltage, it is considered inactivated because it does not allow ion movement. As a result, the cell has an absolute refractory period after each action potential, during which the Nav channels are inactivated and cannot be recruited to initiate another action potential. When the cell repolarizes below the threshold voltage, Nav channels close and transition to a deactivated state before they can open again. Therefore, the maximum firing rate of a neuron is determined by the kinetics of Nav channel inactivation and deactivation.
The driving force of an ion is determined by two factors: electrical and chemical. The electrostatic force is repulsive for similar charges and attractive for opposite charges. For instance, a positive sodium ion (Na+) would be attracted to a negative intracellular voltage. The chemical force, or force of diffusion, is defined by the relative extracellular and intracellular concentrations of the ion. The equilibrium potential is the voltage at which these two forces balance each other, resulting in no net ion flux. When an ion is permitted to move across the membrane, such as when an ion channel is open, the cell will move towards the ion’s equilibrium potential. The equilibrium potential for Na+, which is more concentrated extracellularly, is approximately +60mV. Conversely, the equilibrium potential for K+, which is more concentrated intracellularly, is approximately -85mV. Therefore, the opening of sodium channels is depolarizing, while the opening of potassium channels is hyperpolarizing.
Related Testing for Action Potential
Conduction velocity tests, particularly in peripheral nerves, can identify deficits in action potential transmission. However, further testing is needed to determine the specific mechanism(s) responsible for conduction block or decreased conduction velocity. A decrease in conduction velocity can result from various factors, including injured axons followed by remyelination with short internode lengths, nerve constriction (as seen in carpal tunnel syndrome), or axonal tapering in the distal limbs. Nerve injury, diabetic neuropathy, or demyelination caused by autoimmune disorders such as multiple sclerosis or Guillain-Barré syndrome can also decrease the speed or even block the conduction of electrical signals within nerves.
Pathophysiology of Action Potential
In addition to the conditions mentioned above that can impair conduction in the peripheral nervous system, genetic disorders affecting ion channels (channelopathies) can cause a wide range of pathologies, depending on the tissues where the affected channels are typically expressed. Channelopathies can lead to neuromyotonia, epileptic seizures, migraines, ataxia, and a variety of heart, muscle, or gastrointestinal conditions.
Clinical Significance of Action Potential
Local anesthetics work by blocking voltage-gated sodium channels, thereby preventing the transmission of signals in pain and sensory fibers. Specifically, local anesthetics must pass through the plasma membrane, then bind to and block the channel pore while it is open.
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