Membrane Potential, Resting Potential, and Action Potentials in Giant Squid Axon

Giant squid axon and electrical signaling: key ideas

• Giant squid nerve cells and their axons are unusually large, giving researchers an accessible preparation to study electrical signals in the nervous system.
  • The squid nervous system includes brain and sequential (first, second, and third order) neurons connected in series; the third-order neuron is highlighted in red.
  • The axon diameter is about 800 micrometers, roughly the size of a phone charging cable; this is more than 100 times larger than many human axons, which makes recording and manipulating signals easier.
  • Because of their size, these axons have been used extensively, and continue to be used, to study how electrical signals propagate in neurons.
• Measurements and terminology
  • Membrane potential changes are expressed in millivolts (mV).
  • Stimulation of a neuron is achieved by injecting current into the cell; current is measured in amperes (A).
  • The recording setup can show resting membrane potential and action potentials, as well as different voltage traces depending on the type of stimulation.
  • The bottom axis/trace typically shows the membrane potential; the stimulating current trace is often shown in a different color (e.g., yellow/orange) and can go below zero (negative current).
• Types of membrane potential changes observed in neurons
  • Receptor potential: a depolarization seen in a sensory neuron when it is stimulated by a sensory input.
  • Synaptic potential: a change caused by activation of a synapse; a presynaptic neuron (blue) forms a synapse with the recorded neuron, triggering a potential.
  • Action potential: initiated near the axon hillock (close to the cell body) when a stimulus pushes the membrane potential across the threshold, resulting in a spike.
  • Action potentials are the primary mechanism by which neurons encode information in many pathways.
• A practical application mentioned
  • Local anesthetics used by dentists illustrate how altering membrane potential and nerve excitability can affect sensation and pain.
• Core components that determine membrane potential
  • The membrane must be present to separate inside from outside.
  • Ion channels: selective pores in the membrane that allow specific ions to pass, contributing to permeability.
  • Active transporters (pumps): proteins that bind ions and move them across the membrane against their concentration gradient, consuming energy (e.g., ATP).
  • Passive ion flow through channels: ions move down their electrochemical gradient when channels are open.
  • Ions highlighted: potassium (K⁺), sodium (Na⁺), chloride (Cl⁻) as key contributors to the resting potential and action potential dynamics.
  • The arrangement creates a membrane potential by establishing and maintaining concentration gradients and selective permeabilities.
• Concept of ion gradients and electrochemical gradients
  • Ion concentration gradients (more of some ions on one side of the membrane than the other) are established by pumps and channels.
  • The electrochemical gradient has two components: a chemical gradient (concentration difference) and an electrical gradient (charge difference across the membrane).
  • The net flux of ions is governed by both the gradient and the membrane’s permeability to those ions.
• A simple model to illustrate the setup
  • A membrane separates the inside from the outside of the cell.
  • If potassium channels are permeable to K⁺, K⁺ tends to move down its concentration gradient from inside to outside.
  • At a given membrane voltage, ions may also flow back in the opposite direction if the electrical force opposes the chemical gradient, leading toward an electrochemical equilibrium.
  • Electrochemical equilibrium is the state with no net ion flux.
• Resting membrane potential and multi-ion considerations
  • Real neurons have several ions with unequal intracellular vs. extracellular concentrations (e.g., K⁺, Na⁺, Cl⁻).
  • The resting membrane potential is determined by a combination of gradients and permeabilities of these ions; it is not carried by a single ion, but by their combined influence.
  • A single-ion view (e.g., pure Nernst for K⁺ alone) is insufficient for the resting potential in real neurons.
• How to think about the resting potential with multiple ions
  • The Goldman-Hodgkin-Katz (GHK) framework (a generalization of the Nernst concept) accounts for multiple ions and their permeabilities:
  • Goldmann equation (conceptual form):
  • Vm = rac{RT}{F} \, rac{ igl(P{K}[K^+]o + P{Na}[Na^+]o + P{Cl}[Cl^-]iigr) }{ igl(P{K}[K^+]i + P{Na}[Na^+]i + P{Cl}[Cl^-]_oigr) } \text{(in log form, the full expression uses a natural log or log base 10 with a factor)}
  • In practice, a frequently cited simplified form uses base-10 logarithms and is temperature dependent; the constants change with room vs body temperature, but the qualitative dependence is the same.
  • The resting polarity is dominated by the relative permeabilities and gradients of K⁺, Na⁺, and Cl⁻; at typical mammalian resting states, neurons are about -60 to -70 mV, with -58 mV given as an example in the material.
• Na⁺, K⁺, and Cl⁻ gradients you should know
  • Potassium (K⁺): high inside, low outside; drives resting potential via outward leak when channels are open.
  • Sodium (Na⁺): high outside, low inside; influx during depolarization increases membrane potential toward Na⁺’s equilibrium potential during an action potential.
  • Chloride (Cl⁻): typically higher outside in many neurons; its permeation tends to hyperpolarize but can also contribute to depolarizing events depending on gradients and receptor types.
• How the resting potential is established and maintained
  • Initially, a concentration gradient exists due to pumps moving ions against their gradient (active transporters).
  • Membrane permeability to ions (via channels) determines which ions have the strongest influence on the resting potential.
  • Permeability for potassium is a major driver because K⁺ channels are relatively leaky, promoting K⁺ efflux and negative interior potential.
  • The resting potential is a balance between outward driving force (e.g., K⁺ leaving) and inward driving forces (e.g., Na⁺ entering and Cl⁻ behavior), leading to a steady negative value.
• How changes in permeability or gradients affect the membrane potential
  • If permeability to a particular ion increases (e.g., Na⁺ channels opening during an action potential), the membrane potential shifts toward that ion’s equilibrium potential.
  • When the permeability changes while gradients remain, the attainable range of membrane potentials is anchored by the equilibrium potentials of the ions involved.
  • If the normal line for an ion’s equilibrium potential shifts (e.g., due to altered gradients), the resting or action potential levels shift accordingly.
• The four phases of the action potential (neuron-specific schematic reference)
  • Phase 1: Rising phase (depolarization) – a sharp increase in Na⁺ permeability causes a rapid depolarization toward the Na⁺ equilibrium potential; a sharp spike occurs when threshold is crossed.
  • Phase 2: Peak and early repolarization – Na⁺ channels begin inactivation; Na⁺ influx slows; K⁺ channels begin to contribute to repolarization.
  • Phase 3: Repolarization – increased K⁺ permeability drives the membrane back toward a more negative value.
  • Phase 4: Resting potential and possible hyperpolarization – membrane potential returns to the resting level; there may be a brief hyperpolarization before stabilizing.
• Key conceptual points about action potentials
  • Action potentials are a mechanism by which neurons encode information because they reliably propagate along axons once initiated.
  • The initiation site is typically near the axon hillock where the integration of excitatory/inhibitory inputs occurs.
  • Threshold: a critical level of depolarization that must be reached to trigger an action potential; crossing the threshold engages a positive feedback loop that drives the spike.
• Why the squid preparation remains relevant today
  • It provides an accessible model to illustrate fundamental principles of neuronal signaling that apply across species, including humans.
  • The large size simplifies instrumentation and data collection, helping to elucidate the relationship between membrane potential, ion gradients, and action potentials.
• Connections to broader principles and real-world relevance
  • The interplay between ion gradients and selective permeability is a foundational concept in neurophysiology, linking to topics such as synaptic transmission, neural coding, and pharmacological modulation.
  • Understanding these processes helps explain clinical phenomena like anesthetic action, nerve conduction block, and how neurons communicate across synapses and networks.
• Metaphors and hypothetical scenarios to cement understanding
  • Think of the cell membrane as a selectively permeable barrier with tiny gates (ion channels) and powered pumps (active transporters) that maintain a chemical and electrical balance across the gate.
  • The resting state is like a battery at a steady voltage set by what gates are open most of the time and what ions are available on each side.
  • An action potential is like a coordinated wave of gate openings that travels along the axon, carrying information without diminishing as it propagates.
• Equations and numerical references to memorize
  • Nernst equation (single ion):
  • E{ion} = rac{RT}{zF} \, ext{ln} \left(\frac{[ion]{outside}}{[ion]_{inside}}\right)
  • Simplified (approximate at 37°C):
  • E{ion} \approx \frac{61.5\text{ mV}}{z} \; \log{10} \left(\frac{[ion]{outside}}{[ion]{inside}}\right)
  • Goldman-Hodgkin-Katz (multi-ion, qualitative representation):
  • Vm = \frac{RT}{F} \ln \left( \frac{PK[K^+]o + P{Na}[Na^+]o + P{Cl}[Cl^-]i}{PK[K^+]i + P{Na}[Na^+]i + P{Cl}[Cl^-]_o} \right)
  • Resting membrane potential example: approximately V_m \approx -58 \text{ mV} in the provided slide context.
• Summary takeaway
  • The giant squid axon has been and remains a powerful model for understanding how ion gradients, membrane permeability, and ion transporters shape resting and action potentials.
  • The resting potential emerges from a balance of gradients and permeabilities across multiple ions; action potentials arise from rapid, temporary shifts in permeability (notably Na⁺) that drive the membrane toward the Na⁺ equilibrium potential, followed by K⁺-driven repolarization.
  • This framework connects molecular components (channels and pumps) to macroscopic electrical signals that underlie nervous system function and information processing.