Ion Channels & Electrical Properties of Membranes

Exploring the molecular mechanisms of ion channel function, membrane electrophysiology, and the quantum mechanical foundations of ion selectivity and permeation in biological membranes.

Introduction to Membrane Biophysics

Biological membranes are not passive barriers but dynamic structures equipped with sophisticated protein machinery that controls the flow of ions and molecules. Ion channels are membrane-spanning proteins that form selective pores, allowing specific ions to cross the lipid bilayer at rates approaching the diffusion limit (~10⁸ ions/second).

These channels are essential for numerous physiological processes: nerve impulse transmission, muscle contraction, hormone secretion, sensory transduction, cell volume regulation, and many others. Understanding their structure, function, and regulation requires integrating concepts from electrophysiology, structural biology, quantum mechanics, and computational modeling.

Key Features of Ion Channels

  • Ion Selectivity: Discriminate between similar ions (e.g., K⁺ vs. Na⁺) with ratios >1000:1
  • High Throughput: Conduct ~10⁶-10⁸ ions per second, near diffusion limit
  • Gating: Open and close in response to voltage, ligands, mechanical force, or temperature
  • Regulation: Modulated by phosphorylation, lipids, Ca²⁺, and other factors
  • Pharmacological Targets: Over 13% of approved drugs target ion channels
  • Disease Relevance: Channelopathies affect nerves, muscle, heart, kidney, and more

1. Membrane Potential & Electrochemical Gradients

The electrical potential difference across the plasma membrane, typically -40 to -90 mV (cytoplasm negative), arises from unequal ion distributions maintained by ATP-driven pumps and selective permeability of the membrane to different ions.

The Nernst Equation

For a membrane permeable to a single ion species, the equilibrium potential (Nernst potential) is given by:

$$E_{\text{ion}} = \frac{RT}{zF}\ln\frac{[\text{ion}]_{\text{out}}}{[\text{ion}]_{\text{in}}} = \frac{61.5\,\text{mV}}{z}\log_{10}\frac{[\text{ion}]_{\text{out}}}{[\text{ion}]_{\text{in}}}$$

R = gas constant, T = absolute temperature, z = ion valence, F = Faraday constant. At 25°C, RT/F ≈ 25.7 mV; at 37°C (body temperature), RT/F ≈ 26.7 mV.

Typical Ion Concentrations (mM)

K⁺ inside:~140
K⁺ outside:~5
Na⁺ inside:~12
Na⁺ outside:~145
Cl⁻ inside:~4
Cl⁻ outside:~110
Ca²⁺ inside:~10⁻⁴
Ca²⁺ outside:~2

Calculated Nernst Potentials (37°C)

EK:-90 mV
ENa:+65 mV
ECl:-80 mV
ECa:+130 mV
Typical Vm (resting):-70 mV

The Goldman-Hodgkin-Katz (GHK) Equation

When the membrane is permeable to multiple ion species, the membrane potential is determined by the weighted contributions of each ion according to their permeabilities:

$$V_m = \frac{RT}{F}\ln\frac{P_K[\text{K}^+]_o + P_{\text{Na}}[\text{Na}^+]_o + P_{\text{Cl}}[\text{Cl}^-]_i}{P_K[\text{K}^+]_i + P_{\text{Na}}[\text{Na}^+]_i + P_{\text{Cl}}[\text{Cl}^-]_o}$$

At rest, neurons are most permeable to K⁺ (PK > PNa, PCl), so Vm is close to EK. During an action potential, PNa increases dramatically, driving Vm toward ENa.

Video Lecture Series: The Goldman-Hodgkin-Katz Equation

Part 1: Introduction & Derivation

Introduction to the GHK equation and its derivation from first principles.

Part 2: Multiple Ion Species

Extending the equation to account for multiple ion species and their permeabilities.

Part 3: Applications to Membrane Potential

Practical applications of the GHK equation to calculate resting membrane potentials.

Part 4: Worked Examples & Problem Solving

Step-by-step worked examples and problem-solving techniques using the GHK equation.

The Membrane Potential in Animal Cells Depends Mainly on K⁺ Leak Channels and the K⁺ Gradient

In most animal cells at rest, the plasma membrane is far more permeable to K⁺ than to other ions. This high K⁺ permeability is due to constitutively open K⁺ "leak" channels that are open even at rest, allowing K⁺ to flow down its concentration gradient.

  • K⁺ Leak Channels: Two-pore domain K⁺ channels (K2P) and inward rectifier K⁺ channels (Kir) provide background K⁺ conductance
  • K⁺ Gradient: [K⁺] inside (~140 mM) is much higher than outside (~5 mM), creating a strong driving force for K⁺ efflux
  • Resting Potential: K⁺ efflux through leak channels leaves excess negative charge inside, creating the negative resting potential (-70 mV)
  • Equilibrium Tendency: Vm approaches EK (-90 mV) because PKdominates at rest, but small Na⁺ leak slightly depolarizes the membrane

Key Insight: The resting membrane potential is not simply a passive property but results from the active maintenance of ion gradients by the Na⁺/K⁺-ATPase pump combined with the selective permeability of the membrane to K⁺ through leak channels. This establishes the electrical excitability that underlies nerve and muscle function.

The Resting Potential Decays Only Slowly When the Na⁺-K⁺ Pump Is Stopped

The Na⁺-K⁺-ATPase pump continuously works to maintain the ion gradients that underlie the resting potential, hydrolyzing ATP to pump 3 Na⁺ out and 2 K⁺ in per cycle. What happens if this pump is inhibited?

  • Slow Decay: When the pump is stopped (e.g., by ouabain), the resting potential decays surprisingly slowly—over hours rather than seconds or minutes
  • Low Leak Rate: The lipid bilayer itself is highly impermeable to ions; leak channels conduct ions selectively and at limited rates
  • Large Ion Reservoirs: The cell contains large amounts of K⁺ (~140 mM); losing a small fraction through leak channels has minimal effect on concentration
  • Pump Contribution: The electrogenic pump (3:2 stoichiometry) contributes only ~5-10 mV directly to Vm; its main role is maintaining gradients

Experimental Evidence: Experiments using pump inhibitors show that excitable cells can continue firing action potentials for thousands of cycles even without the pump running, because each action potential involves only tiny changes in ion concentrations. However, without the pump, gradients eventually dissipate and excitability is lost.

Interactive Membrane Equivalent Circuit

The Hodgkin-Huxley equivalent circuit models the plasma membrane as a capacitor (Cm) in parallel with ion-selective conductances (g) and batteries representing Nernst potentials (E).

EXTRACELLULAR (+)Cm~1 µF/cm²+gNaENa+65mV+gKEK-90mV+gLEL-70mVINTRACELLULAR (−)Vm-68.0mVCircuit Equations:Im = Cm(dVm/dt) + ΣIionINa = gNa(Vm - ENa)IK = gK(Vm - EK)IL = gL(Vm - EL)Legend:Variable conductanceBattery (Nernst potential)Capacitor

Opens during depolarization

Dominant at rest

Always open (leak channels)

Calculated Values:

Membrane potential: -68.0 mV

Total conductance: 3.8 mS/cm²

Try This:

  • • Set gK high, gNa low → resting potential (~-70mV)
  • • Increase gNa → depolarization (action potential peak)
  • • High gK, low gNa → hyperpolarization

2. Classes of Ion Channels

Ion channels are classified based on their gating mechanisms—the stimuli that control channel opening and closing.

Voltage-Gated Channels

Open or close in response to changes in membrane potential. Critical for action potentials and electrical signaling in excitable cells.

  • Voltage-Gated Sodium Channels (Nav): Rapid depolarization in action potentials
  • Voltage-Gated Potassium Channels (Kv): Repolarization and regulation of firing
  • Voltage-Gated Calcium Channels (Cav): Ca²⁺ influx for signaling and neurotransmitter release
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN): Pacemaker activity

Ligand-Gated Channels (Ionotropic Receptors)

Open in response to binding of neurotransmitters or other ligands. Mediate fast synaptic transmission.

  • Nicotinic Acetylcholine Receptors (nAChR): Excitatory transmission at NMJ and CNS
  • GABAA and Glycine Receptors: Inhibitory chloride channels
  • Glutamate Receptors (AMPA, NMDA, Kainate): Excitatory transmission, synaptic plasticity
  • Purinergic Receptors (P2X): ATP-gated cation channels

Mechanosensitive Channels

Activated by mechanical forces: membrane stretch, pressure, or touch.

  • Piezo Channels: Mechanosensation, proprioception, touch
  • TRP Channels (TRPV, TRPA, TRPM): Multimodal sensors (mechanical, thermal, chemical)
  • MscL/MscS (bacteria): Osmotic stress response

Other Channel Types

  • Temperature-Gated (TRP channels): Thermosensation (TRPV1 for heat, TRPM8 for cold)
  • Store-Operated Channels (Orai/CRAC): ER calcium store depletion
  • Two-Pore Domain K⁺ Channels (K2P): Background leak conductance
  • Inward Rectifier K⁺ Channels (Kir): Maintain resting potential
  • Calcium-Activated Channels: BK, SK, IK channels; chloride channels (TMEM16)

3. Ion Selectivity Mechanisms

The remarkable ability of ion channels to discriminate between chemically similar ions (e.g., K⁺ vs. Na⁺) with selectivity ratios exceeding 1000:1 while maintaining near-diffusion-limited throughput is one of the most elegant solutions in molecular biology.

Ion Channels Are Ion-Selective and Fluctuate Between Open and Closed States

Ion channels exhibit two fundamental properties that define their function: ion selectivity and gating. Unlike simple pores, ion channels actively discriminate between different ion species and transition stochastically between open (conducting) and closed (nonconducting) conformational states.

Gating Behavior: Individual ion channels do not remain permanently open; they fluctuate rapidly between open and closed states. The fraction of time a channel spends in the open state (open probability, Po) determines the overall conductance and is regulated by voltage, ligands, mechanical forces, or other stimuli.

Selectivity vs. Throughput: Ion channels must balance two seemingly contradictory requirements: high selectivity (discriminating ions that differ in radius by <0.5 Å) and high throughput (conducting ~10⁷-10⁸ ions/second). This is achieved through precisely shaped selectivity filters that stabilize specific ions while allowing rapid conduction.

Molecular Recognition: The selectivity filter acts as a molecular sieve, using backbone carbonyl oxygens, charged side chains, or structured water molecules to create binding sites complementary in size and charge distribution to the permeant ion species.

The Three-Dimensional Structure of a Bacterial K⁺ Channel Shows How an Ion Channel Can Work

The 2003 Nobel Prize-winning work of Roderick MacKinnon and colleagues revealed the atomic structure of the bacterial K⁺ channel KcsA—a landmark achievement that provided the first detailed view of how ion channels achieve their remarkable selectivity and conductance properties.

Structural Features of the K⁺ Channel

  • Tetrameric Architecture: Four identical subunits symmetrically arranged around central pore
  • Transmembrane Helices: Each subunit contributes two α-helices (inner and outer) spanning the membrane
  • Pore Helix & Selectivity Filter: Between transmembrane helices, a pore helix and extended chain form the narrow selectivity filter
  • Water-Filled Cavity: A large central cavity (~10Å diameter) allows hydrated K⁺ ions to approach the selectivity filter from the intracellular side
  • Narrow Selectivity Filter: The 12Å-long filter region contains four K⁺ binding sites (S1-S4) formed by backbone carbonyl oxygens of the signature TVGYG sequence

The crystal structure revealed that the selectivity filter is lined by backbone carbonyl oxygens from the TVGYG motif, which precisely coordinate dehydrated K⁺ ions. This structure explained how the channel achieves exquisite selectivity: the carbonyl oxygens are positioned to exactly mimic the hydration shell of K⁺, but the cavity is too large to stabilize the smaller Na⁺ ion efficiently.

  • Filter Sequence: Highly conserved TVGYG motif forms the selectivity filter
  • Binding Sites: 4 binding sites (S1-S4) within the 12Å filter region
  • Coordination Geometry: 8 carbonyl oxygens coordinate each K⁺ ion
  • Snug Fit Hypothesis: Filter cavity optimized for K⁺ radius (1.33Å) vs. Na⁺ (0.95Å)
  • Knock-On Mechanism: K⁺ ions move in single file; incoming ion pushes outgoing ion

Energetic Balance: The dehydration cost for K⁺ (~75 kcal/mol) is exactly compensated by coordination with filter carbonyls. For Na⁺, the larger dehydration cost cannot be fully compensated, creating a ~3 kcal/mol barrier that explains >10,000:1 selectivity.

Sodium Channel Selectivity

Nav channels face the opposite challenge: selecting Na⁺ (0.95Å) over K⁺ (1.33Å). The DEKA motif forms a narrower selectivity filter.

  • DEKA Locus: Aspartate, Glutamate, Lysine, Alanine residues from four domains
  • Smaller Pore: ~3-4Å diameter vs. ~12Å for K⁺ channels
  • Partial Hydration: Na⁺ retains partial hydration shell while passing through
  • Selectivity: ~10-100:1 for Na⁺ over K⁺

Calcium Channel Selectivity

Cav channels must select Ca²⁺ (1.00Å) over Na⁺ (0.95Å) and K⁺ (1.33Å) despite 1000-fold higher concentrations of monovalent ions.

  • EEEE/EEDD Locus: Ring of negatively charged glutamate residues
  • High-Field-Strength Site: Concentrated negative charge attracts divalent cations
  • Ion-Ion Repulsion: Two Ca²⁺ ions in filter; electrostatic repulsion speeds permeation
  • Selectivity: >1000:1 for Ca²⁺ over monovalent cations

4. Quantum Mechanical Aspects of Ion Permeation

While ion channel function is primarily understood through classical electrostatics and molecular dynamics, quantum mechanical effects contribute to selectivity, binding energetics, and potentially the dynamics of ion permeation.

Quantum Contributions to Selectivity

  • Electronic Structure: Ion-protein interactions involve charge transfer and polarization
  • Zero-Point Energy: Lighter ions (especially protons) have larger quantum fluctuations
  • Tunneling: Protons can tunnel through barriers in H2O wires (water channels)
  • Basis Set Superposition Error: Accurate binding energies require quantum chemical corrections
  • Dispersion Interactions: van der Waals forces important for selectivity (DFT-D methods)

QM/MM Simulations of Ion Channels

Hybrid quantum mechanics/molecular mechanics (QM/MM) approaches treat the selectivity filter quantum mechanically while using classical force fields for the protein and solvent environment.

  • QM Region: Selectivity filter carbonyl oxygens, coordinating water, permeating ions
  • MM Region: Protein backbone, lipid bilayer, bulk solvent
  • Methods: DFT (B3LYP, PBE), post-Hartree-Fock (MP2, CCSD)
  • Insights: Polarization effects, charge transfer, accurate binding free energies
  • Challenges: Computational cost limits system size and sampling time

Proton Channels & Water Wires

Proton channels (aquaporins, M2 channel, bacterial porins) exhibit distinctive quantum behavior due to proton tunneling and delocalization in hydrogen-bonded networks.

  • Grotthuss Mechanism: Proton hopping via H3O⁺ and H-bond rearrangements
  • Proton Tunneling: Quantum tunneling between adjacent water molecules
  • Nuclear Quantum Effects: Path integral molecular dynamics (PIMD) reveals delocalization
  • Kinetic Isotope Effects: H⁺ vs. D⁺ permeation rates differ due to tunneling

5. The Action Potential

The action potential is a rapid, transient reversal of membrane potential that propagates along axons and excitable membranes. It is the fundamental unit of electrical signaling in the nervous system.

The Function of a Nerve Cell Depends on Its Elongated Structure

Neurons are among the most structurally polarized cells in the body, with highly specialized compartments that enable long-distance electrical signaling. The elongated morphology of neurons is intimately linked to their function in transmitting information rapidly over long distances.

Cell Body (Soma)

Contains nucleus and most biosynthetic machinery. Integrates incoming synaptic signals from dendrites.

Dendrites

Highly branched input region. Covered with thousands of synapses receiving signals from other neurons.

Axon Hillock

Site of action potential initiation. High density of voltage-gated Na⁺ channels creates lowest threshold for firing.

Axon

Single long process (up to 1 meter in humans) conducting action potentials. Uniform diameter, few branches until terminal.

  • Directional Signal Flow: Information flows from dendrites → soma → axon hillock → axon → synaptic terminals
  • Axonal Transport: Molecular motors transport proteins, organelles, and neurotransmitters along microtubules
  • Length Scales: Dendrites: tens of micrometers; Axons: millimeters to meters; Total distance: up to 1000× cell body diameter
  • Speed Requirements: To rapidly transmit signals over long distances, neurons evolved action potentials and myelination

Voltage-Gated Cation Channels Generate Action Potentials in Electrically Excitable Cells

The action potential is made possible by voltage-gated Na⁺ and K⁺ channels that open and close in response to changes in membrane potential, creating a regenerative, self-propagating electrical signal.

Voltage-Gated Sodium Channels (Nav)

  • Activation Gate (m-gate): Opens rapidly (~1 ms) when membrane depolarizes past threshold (~-55 mV)
  • Inactivation Gate (h-gate): Closes more slowly (~1-2 ms) after activation, terminating Na⁺ influx
  • Three States: Closed (resting), Open (activated), Inactivated (refractory)
  • Recovery: Must repolarize to negative potentials to remove inactivation and return to closed state
  • Absolute Refractory Period: During inactivation, no stimulus can trigger another action potential

Voltage-Gated Potassium Channels (Kv)

  • Delayed Activation: Opens more slowly than Na⁺ channels (~2-5 ms after depolarization)
  • Sustained Opening: Remains open during depolarization, no fast inactivation
  • Repolarization Role: K⁺ efflux brings membrane back to negative potentials
  • Relative Refractory Period: Hyperpolarization after action potential requires stronger stimulus

The coordinated opening and closing of these voltage-gated channels creates the stereotyped waveform of the action potential: rapid depolarization (Na⁺ influx), brief reversal to positive potentials, rapid repolarization (K⁺ efflux), and hyperpolarization before return to rest.

Phases of the Action Potential

1. Resting Potential (-70 mV):

High K⁺ permeability (leak channels), Na⁺/K⁺-ATPase maintains gradients.

2. Depolarization (threshold → +40 mV):

Voltage-gated Na⁺ channels open, Na⁺ influx rapidly depolarizes membrane.

3. Repolarization (+40 → -70 mV):

Na⁺ channels inactivate, voltage-gated K⁺ channels open, K⁺ efflux repolarizes.

4. Hyperpolarization (undershoot):

K⁺ channels slow to close, membrane briefly more negative than resting.

5. Return to Resting:

Leak channels and Na⁺/K⁺-ATPase restore resting potential.

Hodgkin-Huxley Model

The 1952 Hodgkin-Huxley model (Nobel Prize 1963) mathematically describes action potential propagation using voltage-dependent conductances:

$$C_m\frac{dV}{dt} = -\bar{g}_{\text{Na}}m^3h(V-E_{\text{Na}}) - \bar{g}_K n^4(V-E_K) - g_L(V-E_L) + I_{\text{ext}}$$

m = Na⁺ activation gate, h = Na⁺ inactivation gate, n = K⁺ activation gate. Each gate follows first-order kinetics with voltage-dependent rate constants.

  • Predicts threshold behavior, all-or-none responses, refractory periods
  • Explains propagation velocity (1-100 m/s depending on axon diameter and myelination)
  • Foundation for modern computational neuroscience

Cable Theory & Propagation

Action potential propagation along axons is described by cable equation:

$$\lambda^2\frac{\partial^2 V}{\partial x^2} = \tau\frac{\partial V}{\partial t} + V$$

λ = length constant (space clamp), τ = time constant. Myelination increases λ by insulating axon, allowing saltatory conduction between nodes of Ranvier.

Interactive Axon Cable Model

The cable model represents an axon as a series of RC circuits. Current injected at one point spreads passively along the axon, decaying with distance (length constant λ) and time (time constant τ).

EXTERNAL (r_e)c_mr_mr_i0c_mr_mr_i1c_mr_mr_i2c_mr_mr_i3c_mr_m4INTERNAL (Axoplasm)I injectVoltage vs. DistanceVxλ = 0.3 cmc_m: Membrane cap.r_m: Membrane res.r_i: Axial res.

Higher r_m → longer λ (signal travels farther)

Lower r_i → longer λ (wider axons conduct better)

Lower c_m → faster τ (quicker response)

Cable Parameters:

λ (length constant) = 0.32 cm

τ (time constant) = 10.00 ms

λ = √(r_m/r_i), τ = r_m × c_m

Cable Equation

$$\lambda^2 \frac{\partial^2 V}{\partial x^2} - \tau_m \frac{\partial V}{\partial t} = V$$

Steady-State Solution

$$V(x) = V_0 \, e^{-|x|/\lambda}$$

Myelination Increases the Speed and Efficiency of Action Potential Propagation in Nerve Cells

In vertebrates, many axons are wrapped in myelin, a lipid-rich insulating sheath produced by glial cells (oligodendrocytes in CNS, Schwann cells in PNS). Myelination dramatically increases conduction velocity while reducing energy costs.

Structural Features

  • Multiple wraps (up to 100 layers) of glial membrane
  • Myelin sheaths 1-2 mm long separated by ~1 μm gaps
  • Nodes of Ranvier: unmyelinated gaps with high Nav density
  • Paranodal junctions: seal between myelin and axon

Functional Benefits

  • Increased membrane resistance (Rm)
  • Decreased membrane capacitance (Cm)
  • Increased length constant λ (~100× increase)
  • Decreased time constant τ (faster passive spread)
  • Saltatory Conduction: Action potentials "jump" from node to node rather than propagating continuously, increasing speed from ~1 m/s (unmyelinated) to >100 m/s (myelinated)
  • Energy Efficiency: Fewer Na⁺ and K⁺ ions cross membrane (only at nodes), reducing ATP consumption by Na⁺/K⁺-ATPase by ~100-fold
  • Space Efficiency: Myelinated axons conduct faster than unmyelinated axons of same diameter; achieving same speed without myelin would require ~100× larger diameter
  • Disease Relevance: Demyelinating diseases (Multiple Sclerosis, Guillain-Barré syndrome) cause severe neurological deficits due to slowed/blocked conduction

6. Patch-Clamp Electrophysiology

Patch-clamp recording, developed by Neher and Sakmann (Nobel Prize 1991), allows measurement of ionic currents through single ion channels with pA (picoampere) resolution and sub-millisecond time resolution.

Patch-Clamp Configurations

  • Cell-Attached: Seal on intact cell; minimal disruption
  • Inside-Out: Patch excised; cytoplasmic face accessible
  • Outside-Out: Patch re-sealed; extracellular face accessible
  • Whole-Cell: Break patch; measure total membrane current
  • Perforated Patch: Amphotericin pores; preserve cytoplasm

Measured Parameters

  • Single-Channel Conductance: γ = i/V (typically 1-100 pS)
  • Open Probability: Po (fraction of time open)
  • Gating Kinetics: Opening/closing rates, dwell times
  • I-V Relationship: Voltage-dependent current amplitudes
  • Reversal Potential: Erev for ion identification

Applications & Insights

  • Channel Pharmacology: Drug effects on single channels (blockers, modulators, toxins)
  • Gating Mechanisms: Markov models fit to single-channel kinetics reveal conformational states
  • Disease Mechanisms: Channelopathy mutations alter gating, conductance, or trafficking
  • Structure-Function: Correlate structural features with electrophysiological properties
  • High-Throughput Screening: Automated patch-clamp for drug discovery

Patch-Clamp Recording Indicates That Individual Gated Channels Open in an All-or-Nothing Fashion

One of the most striking discoveries from patch-clamp recordings was that individual ion channels do not gradually increase their conductance—they open and close in discrete, all-or-nothing transitions between fully open and fully closed states.

Single-Channel Observations

  • Channel current switches between discrete levels (0 pA vs. ~2 pA)
  • No intermediate conductance states during transitions
  • Transition time <10 μs (limited by recording bandwidth)
  • Open and closed dwell times vary stochastically

Macroscopic Currents

  • Smooth macroscopic current = sum of many stochastic openings
  • Graded response arises from probability, not gradual opening
  • Voltage changes Po, not single-channel conductance
  • Ensemble averaging reveals kinetic schemes
  • Molecular Interpretation: All-or-nothing gating reflects discrete conformational states of the channel protein—the open state has a defined, stable pore geometry
  • Stochastic Gating: Individual channels open and close randomly, but statistical properties (mean open time, Po) are determined by voltage, ligands, and other factors
  • Two-State Approximation: Simplest model: closed ⇌ open. More complex channels have multiple closed states, open states, and inactivated states
  • Single-Molecule Biophysics: Ion channels were among the first membrane proteins studied at the single-molecule level, paving the way for single-molecule FRET, optical tweezers, and other techniques

7. Channelopathies & Disease

Mutations in ion channel genes cause a diverse spectrum of "channelopathies" affecting the nervous system, heart, muscle, kidney, and other organs. Over 60 human diseases are linked to ion channel dysfunction.

Neurological Channelopathies

  • Epilepsy: SCN1A (Nav1.1), KCNQ2/3 (Kv7.2/3)
  • Migraine: CACNA1A (Cav2.1), SCN1A
  • Ataxia: KCNA1 (Kv1.1), CACNA1A
  • Peripheral Neuropathy: SCN9A (Nav1.7) - pain insensitivity
  • Myasthenia: CHRNA1, CHRNB1 (nicotinic AChR)

Cardiac Channelopathies

  • Long QT Syndrome (LQTS): KCNQ1, KCNH2, SCN5A - arrhythmia, sudden death
  • Brugada Syndrome: SCN5A - ventricular fibrillation
  • Catecholaminergic Polymorphic VT: RYR2 (Ca²⁺ release channel)
  • Short QT Syndrome: KCNH2, KCNQ1, KCNJ2

Muscle Channelopathies

  • Hyperkalemic Periodic Paralysis: SCN4A (skeletal muscle Nav1.4)
  • Hypokalemic Periodic Paralysis: CACNA1S (Cav1.1)
  • Myotonia Congenita: CLCN1 (muscle Cl⁻ channel)
  • Malignant Hyperthermia: RYR1 (sarcoplasmic reticulum Ca²⁺ channel)

Other Channelopathies

  • Cystic Fibrosis: CFTR (chloride channel) - lung, pancreas
  • Bartter Syndrome: KCNJ1 (kidney K⁺ channel) - salt wasting
  • Polycystic Kidney Disease: PKD1, PKD2 (TRP channels)
  • Retinitis Pigmentosa: CNGA1 (retinal cation channel) - blindness

Therapeutic Targeting of Ion Channels

Ion channels are among the most successful drug targets, with >13% of approved drugs modulating channel function.

  • Local Anesthetics: Lidocaine, novocaine block Nav channels
  • Anticonvulsants: Carbamazepine, lamotrigine (Nav), gabapentin (Cavα2δ)
  • Cardiac Antiarrhythmics: Quinidine, flecainide block cardiac Na⁺ and K⁺ channels
  • Calcium Channel Blockers: Amlodipine, verapamil for hypertension, angina
  • Sulfonylureas: Glibenclamide blocks KATP channels for diabetes
  • Benzodiazepines: Diazepam, alprazolam potentiate GABAA receptors

7A. Voltage-Gated Cation Channels Are Evolutionarily and Structurally Related

Despite their distinct ion selectivities and physiological roles, voltage-gated Na⁺, K⁺, and Ca²⁺ channels share a common evolutionary origin and remarkable structural similarity. This superfamily of voltage-gated cation channels arose through gene duplication and divergence, with variations in selectivity filters and regulatory domains producing specialized functions.

Conserved Structural Architecture

All voltage-gated cation channels share core structural features that define the superfamily:

  • Voltage Sensor Domain (VSD): Four transmembrane helices (S1-S4) with positively charged residues (mostly arginines) in S4 that sense voltage changes
  • Pore Domain (PD): S5-S6 helices with intervening P-loop forming the ion conduction pathway
  • Tetrameric Assembly: Four subunits/domains arranged symmetrically around central pore
  • Six-Transmembrane Topology: Each functional unit has 6 transmembrane segments (S1-S6)
  • Voltage Coupling: Conformational changes in VSD (S1-S4) mechanically coupled to pore opening/closing (S5-S6)

Kv Channels (Shaker Family)

  • Architecture: Four separate subunits, each with 6TM (S1-S6)
  • Selectivity: TVGYG signature sequence in P-loop
  • Function: Membrane repolarization, spike frequency adaptation
  • Evolution: Ancestral form; simplest voltage-gated architecture
  • Diversity: 40+ genes in mammals (Kv1-12 subfamilies)

Nav Channels

  • Architecture: Single polypeptide with 4 homologous domains (I-IV), each 6TM
  • Selectivity: DEKA locus (Asp-Glu-Lys-Ala from domains I-IV)
  • Function: Rapid depolarization in action potentials
  • Evolution: Arose by gene duplication/fusion of ancestral Kv-like gene
  • Fast Inactivation: IFM motif (Ile-Phe-Met) in III-IV linker acts as inactivation gate

Cav Channels

  • Architecture: Single polypeptide with 4 domains (I-IV), each 6TM (like Nav)
  • Selectivity: EEEE or EEDD locus (Glu residues from all 4 domains)
  • Function: Ca²⁺ influx for signaling, neurotransmitter release
  • Evolution: Closely related to Nav; diverged ~600 million years ago
  • Auxiliary Subunits: β, α2δ, γ subunits modulate gating and trafficking

HCN Channels (Related Family)

  • Architecture: Four subunits, 6TM each, plus cyclic nucleotide-binding domain
  • Function: Hyperpolarization-activated (opposite voltage dependence)
  • Role: Pacemaker currents (Ih) in heart and neurons
  • Evolution: Diverged early from Kv lineage

Evolutionary Timeline & Key Innovations

~2 billion years ago (Bacteria/Archaea)

Ancestral K⁺-selective channels appear (KcsA-like); tetrameric 2TM architecture

~1.5 billion years ago (Early Eukaryotes)

Fusion of 2TM + voltage sensor → 6TM Kv channels with voltage sensitivity

~600-800 million years ago (Metazoans)

Gene duplication/fusion creates 4-domain Nav and Cav channels; enables fast electrical signaling in early nervous systems

~500 million years ago (Vertebrates)

Diversification into specialized subtypes (Nav1.1-1.9, Cav1-3 families); myelination and saltatory conduction emerge

Sequence and Structural Homology

  • S4 Helix Conservation: The voltage-sensing S4 helix contains conserved Arg residues (R1-R4) at every third position across all voltage-gated channels
  • Pore Loop Homology: Despite different selectivity, the P-loop architecture (pore helix + selectivity filter) is conserved in topology
  • Sequence Identity: Nav and Cav share ~30-40% sequence identity; both share ~20-30% with Kv channels
  • Functional Interconversion: Mutagenesis studies show that changing a few selectivity filter residues can interconvert selectivity (e.g., EEEE → DEKA converts Cav → Nav-like)

8. Computational Modeling of Ion Channels

Computational approaches spanning quantum mechanics to network-level simulations provide insights into channel structure, dynamics, and function that complement experimental methods.

Molecular Dynamics Simulations

  • All-Atom MD: Explicit lipids, water, ions; timescales up to microseconds
  • Coarse-Grained MD: Reduced representation for longer timescales (milliseconds)
  • Enhanced Sampling: Umbrella sampling, metadynamics for free energy landscapes
  • Applications: Gating mechanisms, ion permeation pathways, drug binding
  • Software: GROMACS, AMBER, NAMD, CHARMM, Desmond

Continuum Electrostatics (Poisson-Boltzmann)

  • Poisson-Boltzmann Equation: Electrostatic potential in dielectric continuum
  • Applications: pKa calculations, binding free energies, ion distributions
  • Software: APBS, DelPhi, MEAD
  • Advantage: Computationally efficient for large systems
  • Limitation: Neglects atomic detail and explicit solvent structure

Brownian Dynamics & PNP Simulations

  • Poisson-Nernst-Planck (PNP): Continuum description of ion fluxes
  • Brownian Dynamics (BD): Stochastic trajectories of ions in electrostatic field
  • Applications: Current-voltage relationships, ion flux rates, selectivity
  • Advantage: Bridge between atomic detail and macroscopic currents

Machine Learning Approaches

  • AlphaFold: Protein structure prediction including ion channels
  • Neural Network Potentials: ML force fields for faster MD simulations
  • Graph Neural Networks: Predict drug-channel interactions
  • Transfer Learning: Predict channelopathy effects from sequence
  • Automated Analysis: ML for analyzing patch-clamp data, detecting events

9. Future Directions

Emerging Research Areas

  • Cryo-EM Revolution: Near-atomic resolution structures of channels in multiple states
  • Optogenetics: Light-activated channels (channelrhodopsins) for circuit manipulation
  • Synthetic Biology: Designer channels with novel selectivity and gating properties
  • Nanopore Sequencing: Biological and solid-state pores for DNA/RNA sequencing
  • Quantum Biology: Probing quantum effects in ion selectivity and gating
  • Single-Molecule FRET: Real-time conformational dynamics during gating

Therapeutic Opportunities

  • Precision Medicine: Genotype-guided therapy for channelopathies
  • Pain Management: Selective Nav1.7 blockers for chronic pain
  • Gene Therapy: AAV-mediated delivery of functional channel genes
  • Small Molecule Modulators: State-dependent channel modulators with improved specificity
  • Biologics: Antibodies and peptides targeting extracellular channel domains

📺 Video Lectures

Comprehensive video lectures covering membrane transport, ion channels, and the electrical properties of biological membranes.

Membrane Transport & Electrical Properties of Membranes

A comprehensive lecture covering the fundamental principles of membrane transport and electrical properties of biological membranes. Topics include ion gradients, the Nernst equation, membrane potential, passive and active transport, ion channels, pumps, and the molecular mechanisms underlying electrical signaling in cells. Essential viewing for understanding how cells maintain electrochemical gradients and generate electrical signals.

Topics Covered:

  • Electrochemical gradients and the Nernst equation
  • Membrane potential and the Goldman-Hodgkin-Katz equation
  • Ion channels: structure, selectivity, and gating mechanisms
  • Active transport: Na⁺/K⁺-ATPase and other pumps
  • Passive transport and facilitated diffusion
  • Electrical properties of excitable membranes

Further Reading & Resources

Essential Reading

Ion Channels and the Electrical Properties of Membranes (NCBI)

Comprehensive chapter from "Molecular Biology of the Cell" covering ion channel selectivity, membrane potential, voltage-gated channels, action potentials, myelination, patch-clamp techniques, and evolutionary relationships among voltage-gated cation channels.

Classic Textbooks

  • Hille - Ion Channels of Excitable Membranes (3rd ed, 2001)
  • Ashcroft - Ion Channels and Disease (2000)
  • Aidley & Stanfield - Ion Channels: Molecules in Action (1996)
  • Kandel et al. - Principles of Neural Science (6th ed, 2021)

Key Review Articles

  • Hodgkin & Huxley - "A quantitative description of membrane current..." (1952)
  • Doyle et al. - "The structure of the potassium channel" (1998)
  • MacKinnon - "Potassium channels and the atomic basis of selective ion conduction" (2004)
  • Catterall - "Voltage-gated sodium channels at 60" (2012)

Online Resources

  • IUPHAR/BPS Guide to Pharmacology - Ion Channels database
  • Channelpedia - Comprehensive ion channel resource
  • NeuroML - Computational neuroscience models
  • Membrane Protein Data Bank - 3D structures