Resting Membrane Potential, Graded Potentials & Action Potentials

Homeostasis & Energetic Cost of the Nervous System

• The nervous system must continually expend ATP to preserve the ion distributions that underlie neuronal signaling.
• Maintaining these steady-state conditions is called homeostasis; because the variables constantly fluctuate around a set point, the lecturer also uses the term allostasis (dynamic homeostasis).
• Loss of the Na⁺/K⁺ pump or of the channel complement abolishes the ordered state → ionic gradients collapse, membrane potential disappears, and neuronal function ceases.
• Key idea: resting membrane potential (RMP) is the energetic baseline from which rapid signaling events launch and to which they must quickly return.

Membrane Channels Overview

Leakage (Passive) Channels

• Integral membrane proteins that are always open.
• Allow ions to diffuse down their concentration gradients with no regulation.
• Relative numbers of specific leakage channels (Na⁺ vs K⁺) are one major determinant of each cell type’s average RMP.

Gated Channels

Gates = portions of a protein that can change shape (conformation) to open or close the pore.

1. Mechanically gated
   • Physical deformation of the membrane/protein induces opening.
   • Examples:
     • Stylus pressed against skin → whitened/blanched spot coincides with open mechanoreceptors you consciously feel.
     • Patellar tendon tap → stretch of the receptor opens channels and initiates the knee-jerk reflex.
   • When the mechanical force stops, the gate reassumes the closed shape within milliseconds.
2. Ligand (chemically) gated
   • A ligand = any chemical messenger that binds to the channel protein.
   • Binding produces a weak, transient bond → gate swings open → ions flow.
   • After ligand dissociates the gate recloses; other ligand molecules can re-bind repeatedly while the chemical is present.
   • Ion selectivity varies: some pores pass one species (Na⁺‐only, K⁺‐only, Cl⁻‐only); others pass >1 (e.g., skeletal-muscle acetylcholine receptor passes Na⁺ & K⁺ in different proportions).
3. Voltage gated
   • Conformation depends on membrane voltage (difference in potential energy across the membrane).
   • Small changes in Vm caused by other channels (often ligand or graded potentials) switch them between closed ↔ open states.
   • Principal ions: Na⁺, K⁺, Ca²⁺.

Ionic Distribution & Resting Membrane Potential (RMP)

• Cytosolic (inside) vs interstitial (outside) ion milieu:
  • Outside: high Na⁺, high Cl⁻.
  • Inside: high K⁺ plus many impermeant anions (ATP-derived phosphates, acidic amino acids in cytoskeletal & peripheral membrane proteins).
• Positive charges are nearly balanced across the membrane; the excess negative charge inside gives the interior its net negativity.
• Typical RMP values:
  • Neuron: -70\,\text{mV}.
  • Skeletal muscle: -85 \text{ to } -90\,\text{mV}.
  • Cardiac ventricular myocyte: \approx -90\,\text{mV}.
  • Cardiac pacemaker (spontaneously depolarizing) cells: \approx -60\,\text{mV}.
• Equilibrium arises from the interplay of three processes:
  1. Na⁺ leakage into the cell.
  2. K⁺ leakage out of the cell.
  3. The Na⁺/K⁺-ATPase pumping 3\,\text{Na}^+{\text{in}} \rightarrow \text{out},\; 2\,\text{K}^+{\text{out}} \rightarrow \text{in} per ATP.
• Altering the relative numbers of Na⁺ vs K⁺ leakage channels shifts RMP (e.g., more K⁺ channels in skeletal & cardiac muscle → more negative RMP).

Depolarization & Hyperpolarization (Directional Terms)

• Depolarization: Vm moves toward 0; inside becomes less negative (positive deflection).
• Hyperpolarization: Vm moves further from 0; inside becomes more negative.
• These labels are context-free directional descriptors; magnitude & mechanism are specified separately.

Graded Potentials (Local/Generator Potentials)

• Occur on receptive regions of a neuron (dendrites, soma, sensory endings).
• Initiated by mechanically or ligand-gated channels, not by voltage-gated channels.
• Properties:
  • Localized: largest change at the site of stimulation; charge spreads outward by cytoplasmic diffusion and dissipates with distance.
  • Variable magnitude: amplitude ∝ stimulus strength.
  • Light stylus pressure → small ΔVm.
  • Heavy pressure → open more/longer channels → larger ΔVm.
  • Bidirectional: can be depolarizing (e.g., Na⁺ influx) or hyperpolarizing (e.g., Cl⁻ influx, K⁺ efflux).
  • Decay: internal Na⁺ (or other ion) concentration declines as ions diffuse → Vm falls back toward rest.
• Many graded potentials must summate in space and/or time at the axon hillock to bring that membrane to threshold and trigger an action potential.

Action Potentials (APs)

Voltage–Time Profile

• Axon membrane at rest: -70\,\text{mV}.
• Threshold: \approx -55\,\text{mV} (point of no return).
• Peak: +30\,\text{mV}.
• Duration: \approx 4\,\text{ms} (neuron).
• Phases:
  1. Depolarization (rapid upstroke).
  2. Repolarization (downstroke toward negative).
  3. After-hyperpolarization (brief undershoot below rest).

Voltage-Gated Na⁺ Channel – 3 Functional States

• Two physical gates; never both closed simultaneously.

1. State 1 (Closed-but-activatable)
   • Present at RMP (< threshold).
2. State 2 (Open)
   • Reached immediately when Vm exceeds threshold.
   • Both gates open → massive Na⁺ influx → explosive depolarization to +30\,\text{mV}.
3. State 3 (Inactivated)
   • At the peak (+30 mV) the inactivation gate closes; Na⁺ permeability stops.
   • Channel cannot reopen until Vm falls below threshold, resetting to State 1.

Voltage-Gated K⁺ Channel

• Single gate (simpler).
• Closed at rest; opens more slowly than Na⁺ channel, precisely as Na⁺ channel inactivates.
• Trigger to open: Vm ≈ +30 mV.
• K⁺ efflux → repolarization.
• Closes near -80\text{ to }-90\,\text{mV}, ending hyperpolarization.

Refractory Periods

• Absolute Refractory Period (ARP)
  • From opening of Na⁺ channels (State 2) until they reset to State 1.
  • Vm is above threshold (depolarization + early repolarization).
  • No stimulus, however strong, can evoke another AP because Na⁺ channels are either already open or inactivated.
• Relative Refractory Period (RRP)
  • From restoration of State 1 (Vm < threshold) through the hyperpolarized phase until Vm returns to rest.
  • Possible to fire a new AP, but requires a stronger-than-usual stimulus because Vm starts more negative (e.g., −80 mV) and must climb a longer distance to threshold.
• Functional importance: limits maximal firing rate and shapes frequency coding.

Stimulus Intensity Encoding – Rate Coding

• All APs have identical amplitude/shape (all-or-none).
• The CNS discerns stimulus strength by frequency of APs traveling along a given axon:
  • Weak stimulus → few APs per unit time.
  • Strong stimulus → many APs per unit time.
• Demonstrated with an electrode stimulator:
  • Subthreshold current → 0 APs.
  • At-threshold current → sporadic APs.
  • Higher current → higher AP frequency (but identical waveform).

Conduction Velocity of Action Potentials

• Directly proportional to axon diameter: larger diameter ↓internal resistance → faster current spread under the membrane.
• Enhanced by myelin (provided by oligodendrocytes in CNS, Schwann cells in PNS):
  • Saltatory conduction: AP “jumps” node to node, dramatically increasing speed.
• Clinical relevance: nerve conduction studies (e.g., carpal tunnel syndrome) detect slowed velocities due to compression or demyelination.

Key Examples, Connections & Misc. Points

• Stylus-on-skin: demonstrates mechanically gated channels, graded potentials proportional to pressure.
• Patellar tendon reflex: stretch receptor is a mechanically gated channel initiating an AP that triggers quadriceps contraction.
• Ligand terminology: book may call them “chemically gated” in one chapter and “mechanically gated” later; instructor standardizes on ligand-gated.
• Homeostasis vs Allostasis: used interchangeably in this lecture; technically allostasis emphasizes the dynamic, energy-consuming aspect of maintaining the set point.
• Energy budget: “expensive nervous system” – a significant fraction of brain ATP drives Na⁺/K⁺-ATPase to preserve RMP even in silence.
• Future ties (to be covered next lecture):
  • Categorizing axons by diameter & myelination (Aα, Aβ, Aδ, C, etc.).
  • Details of propagation (domino analogy) and synaptic transmission.
  • How graded potentials at the hillock summate to reach threshold and initiate axonal APs.