Neurophysiology Notes: Resting Membrane Potentials, Graded Potentials, and Action Potentials
Resting Membrane Potentials (RP) and the Foundations of Neuronal Excitability
Resting state basics
Neurons have electrochemical gradients across the membrane, created by unequal ion distributions and charge separation.
Chemical (concentration) gradient: ions such as Na⁺, K⁺, Ca²⁺, Cl⁻ are not equally distributed across the membrane.
Electrical gradient: an unequal distribution of positive and negative charges across the membrane creates a membrane potential (voltage).
By convention, the extracellular fluid (ECF) is defined as 0 mV.
Resting membrane potential (RP or resting Vm) is negative, typically about -60 to -80 mV (often around -70 mV).
Ion distributions at rest (typical values)
Extracellular (outside the cell):
[K⁺]ₑ ≈ 5 mM
[Na⁺]ₑ ≈ 145 mM
[Cl⁻]ₑ ≈ 108 mM
Intracellular (inside the cell):
[K⁺]ᵢ ≈ 150 mM
[Na⁺]ᵢ ≈ 15 mM
[Cl⁻]ᵢ ≈ 10 mM
Proteins inside are negatively charged (A⁻) ≈ 100 mM.
Ca²⁺ has a very small role under resting conditions: [Ca²⁺]ᶦⁿᵗ ≈ 10⁻⁴ mM vs [Ca²⁺]ₑₓₜ ≈ 1 mM.
The Na⁺/K⁺-ATPase (sodium–potassium pump)
Maintains gradients: 3 Na⁺ are pumped out for every 2 K⁺ pumped in.
Requires ATP.
Contributes to the negative internal environment by moving more positive charge out than in.
Why RP is negative
Higher permeability to K⁺ than to Na⁺ at rest: the membrane is more permeable to K⁺, driving the RP toward the K⁺ equilibrium potential (E_K).
Equilibria are not static: Na⁺ and K⁺ ions continue to move across, but the Na⁺/K⁺-ATPase maintains gradients against passive leaks.
EK ≈ -92 mV and ENa ≈ +62 mV; at RP these currents are equal and opposite, stabilized by the pump.
Concept: increasing Na⁺ permeability would shift Vm toward ENa, moving toward depolarization and enabling electrical signaling.
The Nernst equation (single-ion perspective)
Describes the equilibrium potential for a single permeant ion if the membrane were permeable only to that ion.
Formulations:
E{ion} = rac{RT}{zF} \, ext{ln}iggl(\frac{[ion]{out}}{[ion]_{in}}\biggr)
At 37°C, this is often approximated as
E{ion} \approx 61 \; \log{10}\biggl(\frac{[ion]{out}}{[ion]{in}}\biggr) \, \text{mV}
Where: R is the gas constant, T is temperature in Kelvin, F is Faraday's constant, z is the ionic charge.
The Goldman–Hodgkin–Katz (GHK) equation (resting Vm with multiple ions)
Accounts for multiple ions with different permeabilities rather than assuming a single ion.
General form (illustrative):
Vm = 61 \log\left(\frac{PK [K^+]\text{out} + P{Na} [Na^+]\text{out} + P{Cl} [Cl^-]\text{in}}{PK [K^+]\text{in} + P{Na} [Na^+]\text{in} + P{Cl} [Cl^-]_\text{out}}\right)
The value of Vm depends on the relative permeabilities (PK, PNa, P_Cl) and ion concentrations inside and outside.
The equation is for illustrative purposes here and complements the Nernst equation.
Factors that alter RP and Vm
Changes in ion concentrations (both inside and outside).
Changes in relative membrane permeabilities (e.g., opening/closing ion channels).
The Na⁺/K⁺-ATPase continues to maintain gradients to prevent indefinite ion flux.
Alterations in PNa or PK shift Vm toward ENa or EK, respectively, affecting excitability.
Stimulus and transition from RP to electrical signaling
At rest, Vm ≈ -70 mV.
Stimulus can change membrane permeability via channels (chemically gated, voltage-gated, mechanically gated).
Resulting changes in Vm initiate graded potentials, which can summate to reach threshold and trigger action potentials (APs) when conditions are right.
Graded Potentials
What they are
Local, short-distance changes in Vm in dendrites and soma.
Amplitude is variable and proportional to stimulus strength.
They decay with distance and time due to:
Current leak across the membrane
Cytoplasmic resistance to current flow
Hyperpolarization or depolarization as charge separation changes
Characteristics
Decay with distance from the stimulus origin (strongest at the stimulus point; weaker further away).
They occur with neurotransmitter binding at dendrites/cell body causing Na⁺ channels to open and Na⁺ influx, leading to local depolarization.
Usually graded in amplitude and may summate spatially or temporally to influence the trigger zone.
The trigger zone and threshold for action potential generation
Trigger zone located at the axon hillock (beginning of the axon).
Threshold potential is around ≈ -55 mV.
If a graded potential depolarizes the membrane at the trigger zone to threshold, voltage-gated Na⁺ channels open and an action potential is generated.
If the graded potential does not reach threshold, no AP is produced and the graded potential dies out.
Subthreshold vs suprathreshold graded potentials
Subthreshold: graded potential starts above threshold but decays to below threshold by the time it reaches the trigger zone, no AP.
Suprathreshold: graded potential remains above threshold at the trigger zone, producing an AP.
Example schema (conceptual)
Synaptic input at dendrite → Na⁺ channels open → depolarization in dendrite/cell body → graded potential spreads toward axon hillock.
Action Potentials (APs)
Definition and key properties
Large depolarizations (~100 mV) with constant amplitude that do not decay with distance.
All-or-none event: once triggered, AP remains uniform in amplitude and duration as it propagates.
Rapid, long-distance electrical signaling capable of reaching axon terminals and synapses.
Anatomy of the AP (phases and channel behavior)
Resting membrane potential precedes AP (~ -70 mV).
Rising phase (depolarization): rapid Na⁺ entry when voltage-gated Na⁺ channels open.
Peak: Vm approaches +30 mV (briefly) as Na⁺ influx slows and some K⁺ conductance rises.
Falling phase (repolarization): K⁺ channels open; K⁺ leaves the cell, driving Vm back toward negative values.
After-hyperpolarization (AHP): K⁺ channels remain open longer, causing Vm to dip below resting potential briefly before returning to RP.
Voltage-gated Na⁺ channel gating
Two gates in the channel: activation gate (opens rapidly) and inactivation gate (closes more slowly).
At resting potential, the activation gate is closed.
Depolarization opens the activation gate; Na⁺ enters the cell (INa).
Inactivation gate closes shortly after activation (≈ 0.5 ms after activation).
After repolarization, both gates reset to their original positions (requires ≈ 2 ms).
Refractory periods
Absolute refractory period: Na⁺ channels cannot be activated; no AP can be generated.
Prevents AP overlap and backward propagation.
Relative refractory period: some Na⁺ channels are not ready; K⁺ channels are still open.
An AP can be triggered, but requires a larger than normal stimulus and APs are smaller than usual.
Phases in a typical AP cycle (sequence)
Resting → depolarization (Na⁺ channels activate, Na⁺ influx) → peak (Na⁺ channel inactivation) → repolarization (K⁺ efflux) → after-hyperpolarization (continued K⁺ efflux) → return to resting permeability and Vm.
Mechanisms of AP Propagation and Conduction
Propagation concept
An AP in one segment of axon triggers a depolarizing wave in adjacent segments via local current flow.
The passive spread of current depolarizes nearby membrane to threshold, generating a new AP downstream.
Conduction speed and factors that regulate it
In small-diameter axons, APs conduct slowly (≈ ~5 m/s).
Increasing axon diameter increases membrane resistance to ion flow and speeds conduction.
Myelination increases speed by reducing current leakage; ions cross at nodes of Ranvier where voltage-gated Na⁺ channels are concentrated.
Saltatory conduction: APs are generated only at nodes; the electrical impulse appears to jump from node to node, greatly increasing conduction velocity (up to ~150 m/s).
Saltatory conduction in detail
Myelin sheath insulates segments of the axon; current leaks are minimized between nodes.
Nodes of Ranvier contain dense clusters of voltage-gated Na⁺ channels.
In demyelinating diseases, current leaks out of insulated regions between nodes, slowing conduction.
Graphical intuition
A wave of electrical current passes down the axon, with different axonal segments in different phases of the AP simultaneously during conduction.
The refractory region prevents backward conduction of the AP.
Key Equations and Quantitative Concepts
Nernst equation (single ion, idealized)
E{ion} = \frac{RT}{zF} \ln\left(\frac{[ion]{out}}{[ion]_{in}}\right)
At 37°C, often approximated as
E{ion} \approx 61 \log{10}\left(\frac{[ion]{out}}{[ion]{in}}\right) \text{ mV}
Goldman–Hodgkin–Katz (GHK) equation (multion permeability)
Vm = 61 \log\left( \frac{PK [K^+]{out} + P{Na} [Na^+]{out} + P{Cl} [Cl^-]{in}}{PK [K^+]{in} + P{Na} [Na^+]{in} + P{Cl} [Cl^-]_{out}} \right)
Where P_ion are permeabilities for K⁺, Na⁺, and Cl⁻.
Key numerical facts to remember
EK ≈ -92 mV; ENa ≈ +62 mV (at typical intracellular/extracellular values).
RP is typically around -70 mV but ranges from about -60 to -80 mV depending on conditions.
Na⁺/K⁺-ATPase pumps 3 Na⁺ out and 2 K⁺ in per ATP consumed.
Ion Channel Gating and Membrane Dynamics Summary
Activation/inactivation gates in Na⁺ channels
Activation gate opens rapidly in response to depolarization.
Inactivation gate closes more slowly, terminating Na⁺ influx.
After the AP, gates reset to permit another cycle.
K⁺ channels and repolarization
Slow-opening voltage-gated K⁺ channels contribute to repolarization and after-hyperpolarization.
During AP, K⁺ efflux restores negative Vm and helps terminate the spike.
Triggering and initiation of APs
The trigger zone (axon hillock) contains many voltage-gated Na⁺ channels.
Threshold ≈ -55 mV is the critical membrane potential needed to trigger an AP.
If a graded potential reaches threshold at the trigger zone, an AP is generated; otherwise, no AP occurs.
Neuropharmacology and Neuropathology (Applied Contexts)
Neurotoxins and their targets
Local anesthetics (e.g., Novocaine, lidocaine): Block voltage-gated Na⁺ channels.
Maurotoxin (MTX): Blocks some subtypes of voltage-gated K⁺ channels.
Tetrodotoxin (TTX): Blocks some subtypes of voltage-gated Na⁺ channels.
Potassium imbalances and RP/Excitability
Hypokalemia (low [K⁺] in blood): RP becomes more negative (more polarized); APs initiated less readily.
Hyperkalemia (high [K⁺] in blood): RP becomes less negative (less polarized); APs initiated more readily.
Drugs (e.g., loop diuretics, thiazides) can induce hypokalemia by increasing renal K⁺ loss; supplementation may be required.
KCl and clinical/toxic uses
High extracellular K⁺ from KCl can collapse the electrochemical gradient maintained by the Na⁺/K⁺ pump, stopping electrical activity, notably in the heart (used in lethal injection).
Low-dose KCl is used clinically to treat hypokalemia under strict protocols.
Practical notes from the lecture visuals
In saltatory conduction, conduction speed is greatly increased by myelination; conduction can reach ~150 m/s.
In demyelinating diseases, the conduction slows due to current leakage between nodes of Ranvier.
Quick Concept Checks (based on figures and questions in the transcript)
Graded potentials distribution on a neuron
Amplitude is strongest at the site of origin (the stimulus point) and decays with distance along the neuron due to current leak and cytoplasmic resistance.
AP anatomy cue: sequence of voltage changes and channel activity
Rising phase: rapid Na⁺ entry via opening of Na⁺ channels.
Peak: Na⁺ channels inactivate; Na⁺ entry halts.
Falling phase: K⁺ channels open; K⁺ exits, driving repolarization.
After-hyperpolarization: continued K⁺ efflux causes Vm to dip below RP before stabilizing.
Propagation and refractory period implications
The refractory periods prevent backward propagation and AP overlap, ensuring unidirectional signaling.
Connections and Practical Relevance
Foundational principles
The RP arises from the interplay of ion gradients, membrane permeabilities, and active pumps, illustrating how chemistry underpins electrical signaling.
Graded potentials provide a graded input to integrative centers, while APs provide reliable, all-or-none long-distance signaling.
Real-world relevance
Understanding saltatory conduction helps explain why myelinated neurons conduct signals faster and how demyelinating diseases affect nerve function.
Pharmacological agents targeting Na⁺ and K⁺ channels modulate pain, anesthesia, and can be life-saving or dangerous depending on context.
Potassium balance is critical for cardiac and neural function; disruptions can have serious clinical consequences.
Connections to Foundational Principles and Real-World Relevance
The membrane potential is a balance of electrochemical forces: diffusion (concentration gradients) and electromotive forces (voltage differences) moderated by channel permeabilities and pumps.
Electrical signaling in neurons is an example of integrating input (graded potentials) to produce a reliable output (AP), with spatial and temporal summation shaping neural computation.
Myelination and ion channel localization illustrate how biology optimizes signal propagation for speed and efficiency, with direct implications for neurological diseases and therapeutic strategies.
Mathematical notes for reference
Nernst potential for a monovalent ion (approximation):
E{ion} = \frac{RT}{zF} \ln\left(\frac{[ion]{out}}{[ion]{in}}\right) \quad \text{(often approximated as } E{ion} \approx 61 \log{10}\left(\frac{[ion]{out}}{[ion]_{in}}\right) \text{ mV)}
Goldman–Hodgkin–Katz potential (membrane potential):
Vm = 61 \log\left( \frac{PK [K^+]{out} + P{Na} [Na^+]{out} + P{Cl} [Cl^-]{in}}{PK [K^+]{in} + P{Na} [Na^+]{in} + P{Cl} [Cl^-]_{out}} \right)
Summary of Key Points
RP is negative due to stronger K⁺ permeability and active pumping that maintains gradients; the exact Vm results from the balance of gradients and permeabilities.
Graded potentials are the initial, variable signals in dendrites and soma that can summate to reach threshold at the trigger zone.
An AP is a rapid, all-or-none event driven by voltage-gated Na⁺ and K⁺ channels, with distinct phases and refractory periods that govern timing and propagation.
Propagation speed is enhanced by increasing axon diameter and, more effectively, by myelination which enables saltatory conduction at nodes of Ranvier.
Neuropharmacology and neuropathology contexts illustrate how channel function and ion homeostasis are central to health and disease.