Action Potentials
Chpt. 4: The Action Potential
Definition and Synonyms:
Action Potential: Also known as a spike or nerve impulse, the action potential refers to the rapid, transient changes in membrane potential that constitute the basis for the transmission of signals in neurons and other excitable cells. It involves a rapid depolarization followed by repolarization and transient hyperpolarization. Neurons are described as "firing" during this process, generating an "all-or-none" electrical signal.
Purpose of the Action Potential:
The primary purpose is to convey information over long distances within the nervous system without decrement in signal strength. This allows for rapid and precise communication between different parts of the brain and body, facilitating complex functions like thought, movement, and sensation.
Key Ingredients:
Essential components involved in generating the action potential include:
Voltage-sensitive Na⁺ channels: Proteins embedded in the neuronal membrane that open rapidly in response to specific changes in membrane potential, allowing Na⁺ ions to rush into the cell.
Voltage-sensitive K⁺ channels: Proteins that open with a delay compared to Na⁺ channels, allowing K⁺ ions to exit the cell, playing a crucial role in repolarization.
Phases of the Action Potential:
The various phases observed during an action potential, including resting potential, rising phase, peak, falling phase, and undershoot, can be explained by precisely timed changes in membrane permeability to Na⁺ and K⁺ ions, mediated by the opening and closing of their respective voltage-gated channels.
Membrane Permeability:
The permeability of the neuronal membrane to specific ions is dynamically regulated during an action potential, primarily determined by the presence, number, and transient state (open, closed, inactivated) of ion channels selective for those ions.
Information Encoding by Axons:
Axons convey information not just by the presence or absence of action potentials, but through a sophisticated code that includes:
Frequency of firing: A higher rate of action potentials often indicates a stronger stimulus or greater intensity of information.
Timing: The precise timing of action potential generation can convey information, especially in sensory processing.
Pattern of firing: Specific sequences or bursts of action potentials can encode complex neural messages.
Propagation Directionality:
Action potentials typically propagate unidirectionally down the axon (from cell body to axon terminal) due to the transient inactivation of voltage-gated Na⁺ channels immediately after the action potential passes through a segment of the membrane. This inactivation prevents a backward spread of depolarization.
Role of Myelin:
The myelin sheath, a fatty insulation around many axons, serves the purpose of dramatically speeding up the conduction of the action potential along the axon. It forces the electrical signal to "jump" between unmyelinated gaps called Nodes of Ranvier, a process known as saltatory conduction.
Intracellular Recording of Action Potentials
An intracellular recording of an action potential displays the rapid and transient changes in membrane potential over time, visually representing the electrical activity of a neuron.
Axes:
The independent variable (time, often in milliseconds) is typically plotted on the X-axis.
The dependent variable (voltage, in millivolts) is plotted on the Y-axis.
Units of Measurement:
Voltage is measured in millivolts (mV), reflecting the potential difference across the membrane.
Time is usually measured in milliseconds (ms), capturing the rapid kinetics of the event.
Membran e Permeability Changes:
Each distinct phase of the action potential (resting, depolarization, repolarization, hyperpolarization) precisely corresponds to specific, sequential changes in the permeability of the membrane to Na⁺ and K⁺ ions due to the activity of voltage-gated channels. It is essential to be able to draw and label the action potential, indicating its phases and explaining the underlying ionic basis for each.
Phases of the Action Potential
1. Resting State:
Before an action potential begins, the neuron is at its resting membrane potential, typically around -70 mV.
The membrane is more permeable to K⁺ ions (via K⁺ leak channels) than Na⁺ ions, keeping the potential close to the K⁺ equilibrium potential.
All voltage-gated Na⁺ and K⁺ channels are closed.
2. Threshold Depolarization:
A depolarizing stimulus (often a graded potential) causes the membrane potential to rise from its resting state.
If this depolarization reaches a critical level, known as the threshold potential (typically around -55 mV), voltage-gated Na⁺ channels rapidly open, initiating the action potential.
3. Rising Phase (Depolarization):
Initiated when the threshold is reached, leading to the rapid opening of voltage-gated Na⁺ channels.
A massive influx of positively charged Na⁺ ions into the cell occurs, driven by both the electrical and concentration gradients.
This inward current causes rapid and significant depolarization, making the inside of the membrane more positive.
4. Peak of Action Potential (Overshoot):
Occurs as the membrane potential rapidly approaches the Na⁺ equilibrium potential (approximately +60 mV). The potential even briefly "overshoots" past 0 mV.
At this point, two critical events happen:
Voltage-gated Na⁺ channels close and become inactivated (an inactivation gate blocks the pore), preventing further Na⁺ influx.
Voltage-gated K⁺ channels, which were slowly opening in response to the initial depolarization, are now fully open.
5. Falling Phase (Repolarization):
With Na⁺ channels inactivated, the rapid outward flow of K⁺ ions through the now fully open voltage-gated K⁺ channels dominates.
This efflux of positive charges rapidly repolarizes the membrane, bringing the membrane potential back towards negative values.
6. Undershoot (After-Hyperpolarization):
Mechanism: Voltage-gated K⁺ channels are slow to close, allowing K⁺ efflux to continue even after the membrane potential has returned to the resting level.
This excessive K⁺ efflux causes the membrane to briefly become more negative than the resting potential, approaching the K⁺ equilibrium potential (typically around -80 mV).
Absolute Refractory Period: During the rising and early falling (repolarization) phases, voltage-gated Na⁺ channels are either open or inactivated. During this period, it is impossible to generate another action potential, regardless of the stimulus strength. This ensures unidirectional propagation.
Relative Refractory Period: Occurs during the late falling phase and the undershoot. Voltage-gated K⁺ channels remain open, hyperpolarizing the membrane, and many voltage-gated Na⁺ channels are recovering from inactivation (deinactivated). A subsequent action potential can occur, but it requires a stronger-than-normal depolarizing stimulus to reach the threshold due to the membrane's hyperpolarized state.
7. Return to Resting Potential:
As the slow-closing voltage-gated K⁺ channels finally close, the membrane permeability returns to its resting state, primarily governed by K⁺ leak channels.
The Na⁺/K⁺ pump continuously works to maintain the ion concentration gradients that are essential for setting and restoring the resting membrane potential in the long term, although it does not directly contribute to the rapid changes during the action potential itself.
Hodgkin and Huxley Model
Developed by Alan Hodgkin and Andrew Huxley in the 1950s, their groundbreaking research using the Squid Giant Axon proposed that action potentials could be understood entirely through dynamic variations in membrane permeability to both K⁺ and Na⁺ ions. They utilized the voltage clamp technique to precisely control the membrane potential and measure the resulting ionic currents, allowing them to deduce the properties of the underlying voltage-sensitive ion channels.
Their model mathematically described the kinetic properties of these channels, providing the foundation for modern neuroscience.
Voltage-Sensitive Ion Channels
Voltage-Sensitive Na⁺ Channels:
These channels are characterized by rapid activation (opening) in response to membrane depolarization, typically within fractions of a millisecond.
They possess a fast inactivation gate that causes them to close and become inactivated shortly after opening, effectively blocking the pore, even if the membrane remains depolarized. They remain temporarily unable to reopen until the membrane repolarizes to a sufficient negative potential, allowing the inactivation gate to reopen and the channel to reset to a closed, activatable state.
Voltage-Sensitive K⁺ Channels:
These channels exhibit a delayed activation (opening) in response to depolarization compared to Na⁺ channels. This delay is crucial for allowing the Na⁺-driven depolarization to fully occur before K⁺ efflux contributes to repolarization.
They close relatively slowly as the membrane potential returns to resting levels, contributing to the undershoot (after-hyperpolarization).
Understanding Referencing and Experimentation
Blocked Channels:
If voltage-gated Na⁺ and K⁺ channels had identical kinetics (opened and closed simultaneously), or if either channel type were absent or non-functional, it would lead to profound and detrimental changes in action potential generation and propagation, fundamentally altering neuronal signaling.
TTX (Tetrodotoxin):
This potent neurotoxin, found in pufferfish, specifically blocks voltage-gated Na⁺ channels. If TTX is applied to a neuron, it would completely prevent the rising phase of the action potential, thus blocking action potential generation and propagation altogether. This demonstrates the indispensable role of Na⁺ channels in initiation.
TEA (Tetraethylammonium):
This substance specifically blocks voltage-gated K⁺ channels. If TEA is applied, the repolarization phase would be significantly prolonged, and the action potential would broaden substantially, with no distinct undershoot. This highlights the critical role of K⁺ efflux in rapid repolarization and setting the refractory period.
Membrane Potential and Homeostasis
Returning to Resting Potential:
Although essential for maintaining the long-term ion gradients, the Na⁺/K⁺ pump does not directly or rapidly return the membrane to resting potential immediately after an action potential. Instead, the efflux of K⁺ ions through voltage-gated K⁺ channels during the falling phase and undershoot, followed by the closure of these channels and the dominance of K⁺ leak channels, actively drives the membrane back to its resting state.
The undershoot, or after-hyperpolarization, is directly linked to the prolonged opening and continued efflux of K⁺ through voltage-gated K⁺ channels, with the membrane transiently becoming highly permeable to K⁺ at this time.
Permeability and Ion Movement:
Upon returning to resting conditions, voltage-gated Na⁺ channels are inactivated and then closed, allowing the high permeability due to K⁺ leak channels to re-establish and stabilize the resting potential, typically around -70 mV (not -80 mV, as -80 mV is closer to the K⁺ equilibrium potential and reached during hyperpolarization).
Nernst and Goldman Equations
Nernst Equation:
E{ion} = \frac{61.5}{z} \log \frac{[ion]{out}}{[ion]{in}} where E{ion} is the equilibrium potential for a specific ion, z is the charge of the ion. It is used to calculate the equilibrium potential for a single ion species across a membrane, assuming the membrane is exclusively permeable to that ion. This is approximately true for K⁺ at rest, making the resting potential primarily influenced by K⁺ permeability.
Goldman Equation (Goldman-Hodgkin-Katz equation):
This equation is a more complex formula needed during dynamic events like action potentials when the membrane permeability changes significantly to multiple ions (e.g., Na⁺ and K⁺). It takes into account the permeability AND concentration gradients of all relevant ions, providing a more accurate calculation of the membrane potential under varying permeability conditions.
Investigating Permeability Changes
Understanding whether resting membranes are permeable to a specific ion (e.g., Na⁺) can be assessed by observing the change in membrane potential when the extracellular concentration of that ion is altered. For instance, if the membrane potential becomes more positive when extracellular sodium is increased, it indicates that the membrane has some resting permeability to Na⁺.
Properties of Action Potentials and Graded Potentials
Features of Graded Potentials:
Variability: They can be either depolarizing (excitatory postsynaptic potentials, EPSPs) or hyperpolarizing (inhibitory postsynaptic potentials, IPSPs) depending on the type of stimulus (e.g., neurotransmitter binding to ligand-gated channels).
Variable Amplitude and Duration: Their strength and duration are directly proportional to the strength and type of the input stimulus.
Summation: Graded potentials can summate both spatially (multiple inputs at different locations simultaneously) and temporally (multiple inputs from the same source closely spaced in time).
Decremental Conduction: They diminish in strength and amplitude over distance as current leaks out of the membrane, hence they are suitable for short-distance communication.
Features of Action Potentials:
All-or-None: Once the threshold is reached, an action potential fires with a maximal, uniform amplitude and duration, regardless of the strength of the initiating stimulus.
Depolarizing: Always result in a rapid depolarization followed by repolarization and brief hyperpolarization.
Short Duration: Typically last only a few milliseconds.
Voltage-Gated Channel Reliance: Entirely dependent on the precise sequence of opening and closing of voltage-gated Na⁺ and K⁺ channels.
Non-decremental Propagation: Propagate without losing strength over long distances, regenerating themselves at each segment of the axon.
Key Differences:
Action potentials are active, regenerative signals that propagate without decrement over long distances, utilizing voltage-gated channels. In contrast, graded potentials are passive, decremental signals that summate and travel short distances, primarily using ligand-gated or mechanically-gated channels.
Conduction Velocity Factors
Influencing Factors:
Axon Diameter: Thicker axons offer less internal resistance to current flow (lower internal resistance, R_i), allowing depolarization to spread more rapidly along the axon. Thus, higher axon diameter increases conduction velocity.
Myelination: The presence of a myelin sheath significantly increases conduction velocity.
Myelin Function:
Myelin acts as an electrical insulator, reducing current leakage across the membrane. This forces the action potential to "jump" from one Node of Ranvier (unmyelinated gap) to the next, a process called saltatory conduction. This skipping mechanism is much faster than continuous conduction along an unmyelinated axon because ion channels only need to be activated at the nodes, saving time and metabolic energy.
Neurotransmission and Graded Potentials
Role of Graded Potentials: Graded potentials serve as the primary inputs originating from sensory neurons or synaptic connections. They summate at the axon hillock (the trigger zone of the neuron), and if their combined depolarization reaches the threshold, they initiate an action potential, demonstrating the crucial relationship between these two types of electrical signals.
Review of the Action Potential Cycle
The action potential showcases a bipolar nature, transitioning from depolarization to repolarization while ensuring unidirectionality through the refractory periods. It is a fundamental process for rapid and reliable neuronal communication.
Experiments for Insights: By injecting controlled electrical currents (e.g., depolarizing current) and measuring the resulting membrane potential changes, researchers can effectively identify action potentials, study their properties (e.g., threshold, amplitude, refractory periods), and investigate the underlying ionic mechanisms.
Key Definitions
Membrane Potential:
The electrical potential difference (voltage) across a cell membrane, typically negative inside relative to outside at rest.
Equilibrium Potential:
The theoretical membrane potential at which the net electrochemical force for a particular ion across the membrane is zero, meaning there is no net movement of that ion across the membrane, achieving electrochemical equilibrium. It is determined by the ion's concentration gradient and its charge.
Permeability:
Refers to the ease or ability of ions to move across a membrane, directly influenced by the number and state (open/closed) of ion channels within that membrane for specific ions.
Ohm's Law:
The fundamental relationship describing the flow of electrical current: I=V/R or V=IR, where voltage (V) is the product of current (I) and resistance (R). In biological terms, current flow across a membrane is proportional to the driving force (voltage difference) and the membrane's conductance (inverse of resistance).
Current (I):
The flow of electric charge, conventionally defined as moving in the direction of positive charges. In neurons, it refers to the movement of ions across the cell membrane.
Electrochemical Gradient:
The combined force that drives the movement of an ion across a membrane, resulting from both the concentration difference (chemical gradient) and the electrical potential difference (electrical gradient) across that membrane.
Conclusion
Understanding the intricate mechanics of the action potential, including the precise and sequential roles of voltage-gated Na⁺ and K⁺ channels, the implications of their kinetic differences, and the influences on conduction velocity, is absolutely crucial for grasping the fundamental principles of neuronal signaling dynamics. The efficiency, speed, and reliability of neural communication throughout the nervous system directly relate to these well-coordinated biophysical principles.