Ion Channels & Membrane Physiology
Ion Channels & Membrane Physiology
What You'll Learn
- Electrolyte gradients — intracellular vs extracellular concentrations of Na+, K+, Ca2+, Cl−; Nernst equation gives equilibrium potential for each ion; Goldman equation determines resting membrane potential
- Resting membrane potential — approximately −70 mV, set primarily by K+ leak channels; Na+/K+ ATPase is electrogenic (3 Na+ out, 2 K+ in)
- Ion channel types — voltage-gated (Na+, K+, Ca2+), ligand-gated (nAChR, NMDA, AMPA, GABA-A, glycine), mechanically-gated, leak channels; alpha subunit = pore-forming
- Nav channel subtypes — Nav1.1–Nav1.9 with distinct tissue distributions and channelopathies (SCN1A = Dravet, GEFS+); blocked by TTX, local anesthetics, antiepileptics
- Calcium channel subtypes — L/N/P-Q/R/T types; P/Q antibodies = Lambert-Eaton; T-type = absence seizures (ethosuximide)
- Channelopathies — periodic paralysis, episodic ataxias, myotonias, epilepsies; know gene-channel-phenotype associations
- Drugs targeting ion channels — antiepileptics, local anesthetics, toxins, and their specific channel targets
HighYield Pearls
- Resting potential set by K+: RMP ≈ −70 mV sits between EK (−90) and ENa (+60) because K+ leak channels (Kir, K2P) dominate permeability; Na/K ATPase (3 Na out / 2 K in) maintains gradients and is electrogenic.
- Action potential phases: threshold ≈ −55 mV → voltage-gated Nav open (depolarize to ~+30) → Nav h-gate inactivates (absolute refractory) → Kv open slowly (repolarize) → hyperpolarizing undershoot (relative refractory, K still open).
- Na-channel-blocker paradox in epilepsy: AVOID Na blockers (PHT, CBZ, OXC, LTG) in SCN1A Dravet (LoF) and late-onset SCN2A (LoF); they HELP in SCN8A and early-onset SCN2A/KCNQ2 (GoF).
- T-type Ca in absence: low-threshold thalamic T-type (CACNA1H) drives 3-Hz spike-wave bursts → ETHOSUXIMIDE is first-line (also valproate, zonisamide).
- P/Q calcium channels = LEMS: presynaptic voltage-gated Ca channel (CACNA1A / P/Q) antibodies cause Lambert-Eaton; same gene mutations cause familial hemiplegic migraine, EA2, and SCA6.
- Channelopathy triads: Andersen-Tawil (KCNJ2) = periodic paralysis + ventricular arrhythmia + dysmorphism; EA1 (KCNA1) = myokymia + episodic ataxia; CACNA1S = hypokalemic periodic paralysis ± MH susceptibility.
- Myotonia channels: CLCN1 (chloride) → myotonia congenita (Thomsen AD, Becker AR, warm-up phenomenon); SCN4A → paramyotonia congenita (cold/exercise worsens) and hyperkalemic periodic paralysis.
- NMDA gating: requires BOTH glutamate + glycine (coagonist) AND depolarization to relieve Mg2+ block; blocked by ketamine, PCP, dextromethorphan, memantine; anti-NMDA encephalitis = NR1 antibodies.
- HCN/Ih: hyperpolarization-activated, non-selective cation pacemaker current in SAN, thalamic relay neurons, and brainstem; ivabradine blocks SAN HCN.
- Aquaporin-4 = NMOSD target: AQP4 IgG binds astrocytic foot processes → optic neuritis + LETM; MOG and MS are distinct.
🔍 Quick ReferenceChannel / ion · AP phases / kinetics · Channelopathy / drug
Channel / ion
- K+ leak (Kir, K2P) → sets resting membrane potential near EK (−90 mV)
- Na/K ATPase (3 Na out / 2 K in) → electrogenic pump maintaining ion gradients (~−5 to −10 mV contribution)
- Inward rectifier Kir → passes K+ inward more than outward; stabilizes RMP
- HCN (Ih, “funny current”) → hyperpolarization-activated pacemaker in SAN, thalamus, brainstem
- L-type Ca (Cav1, DHPR) → skeletal EC coupling, smooth muscle tone, neuroendocrine; nimodipine in SAH
- P/Q-type Ca (CACNA1A) → dominant presynaptic Ca channel at NMJ — LEMS antibody target
- T-type Ca (CACNA1H) → low-threshold thalamic burst firing — absence seizures (ethosuximide)
- NMDA receptor → Na/Ca/K flux; Mg2+ block; needs glutamate + glycine coagonist + depolarization
- AMPA receptor → fast Na/K EPSP — perampanel antagonist
- GABA-A / glycine → ligand-gated Cl− influx → hyperpolarizing inhibition
- AQP4 → astrocytic foot-process water channel; NMOSD IgG target
- Connexin GJB1 → gap-junction protein; mutated in CMT-X
AP phases / kinetics
- Threshold ≈ −55 mV → Nav activation gate (m-gate) opens → regenerative Na+ influx
- Depolarization to ~+30 mV → approaches ENa as PNa briefly exceeds PK
- Nav inactivation (h-gate closes) → absolute refractory period — no AP regardless of stimulus
- Delayed Kv opening → K+ efflux → repolarization back toward EK
- Afterhyperpolarization (undershoot) → K channels still open → relative refractory period
- GHK equation → weighted permeabilities of Na/K/Cl set actual membrane voltage
- Nernst equation → equilibrium potential for a single ion (EK ≈ −90, ENa ≈ +60, ECa ≈ +120)
- Saltatory conduction → Nav clustered at nodes of Ranvier; faster + energetically efficient propagation
Channelopathy / drug
- SCN1A LoF → Dravet syndrome — AVOID Na+ channel blockers (worsen seizures)
- SCN2A (bidirectional) → early GoF → Na blockers help; late LoF → AVOID Na blockers
- SCN8A GoF → EIEE; high-dose Na blockers (PHT, CBZ) may help
- SCN4A → hyperkalemic periodic paralysis, paramyotonia congenita
- SCN5A → LQT3 and Brugada syndrome
- KCNQ2/3 → benign familial neonatal seizures (BFNS); KCNQ2 also EIEE
- KCNJ2 → Andersen-Tawil: periodic paralysis + ventricular arrhythmia + dysmorphism
- KCNA1 → episodic ataxia type 1 with myokymia
- KCNT1 → MMPSI / sleep-related hyperkinetic epilepsy — quinidine tried
- CACNA1A → familial hemiplegic migraine, episodic ataxia 2, SCA6
- CACNA1S → hypokalemic periodic paralysis ± malignant hyperthermia
- CLCN1 → myotonia congenita (Thomsen AD, Becker AR — warm-up phenomenon)
- RYR1 / RYR2 → malignant hyperthermia + central core disease / CPVT
- CASPR2 / VGKC complex antibodies → Isaacs neuromyotonia (continuous motor unit firing)
- Lidocaine / class Ib antiarrhythmics → bind Nav open/inactivated state; mexiletine used for myotonia
- Lacosamide → enhances SLOW inactivation of Nav (distinct from PHT/CBZ fast inactivation)
- Ethosuximide / zonisamide → block T-type Ca channels → absence seizures
- Benzodiazepines & barbiturates → positive allosteric modulators of GABA-A (frequency vs duration of Cl channel opening)
- Ketamine / memantine / PCP → NMDA channel blockers (use-dependent)
- Perampanel → noncompetitive AMPA receptor antagonist
Electrolyte Concentrations & Membrane Equations
Intracellular vs Extracellular Ion Concentrations
| Ion | Intracellular (mM) | Extracellular (mM) | Equilibrium Potential (Eion) | Direction at Rest |
|---|---|---|---|---|
| K+ | ~140 | ~4 | −90 mV | Outward (down concentration gradient) |
| Na+ | ~15 | ~145 | +60 mV | Inward |
| Ca2+ | ~0.0001 | ~2 | +120 mV | Inward |
| Mg2+ | ~0.5 | ~1 | — | Variable; blocks NMDA channel at rest |
| Cl− | ~5–15 | ~110 | −70 to −80 mV | Inward (in most adult neurons) |
| HCO3− | ~12 | ~24 | −33 mV | Outward through GABA-A channels |
Nernst Equation
- Purpose: calculates the equilibrium (reversal) potential for a single ion
- Formula: Eion = (RT/zF) × ln([ion]out / [ion]in)
- At 37°C, simplified: Eion = (61.5/z) × log10([ion]out / [ion]in)
- Equilibrium potential = voltage at which there is no net movement of that ion
Goldman-Hodgkin-Katz (GHK) Equation
- Purpose: determines the resting membrane potential considering the relative permeability to multiple ions
- Accounts for Na+, K+, and Cl− with their respective permeabilities (P)
- At rest, PK >> PNa (~40:1) → resting potential is closest to EK
- During an action potential, PNa briefly exceeds PK → membrane approaches ENa
Board Pearl
The resting membrane potential (−70 mV) is closest to EK (−90 mV) because K+ permeability dominates at rest. It is not exactly EK because of small Na+ leak inward. Hyperkalemia depolarizes the resting membrane → initial hyperexcitability, then inexcitability (depolarization block).
Resting Membrane Potential
Key Determinants
- K+ leak channels (two-pore domain, K2P) — primary determinant; open at rest, allowing K+ efflux
- Na+/K+ ATPase — pumps 3 Na+ out and 2 K+ in per cycle = net loss of 1 positive charge = electrogenic (contributes ~−5 to −10 mV)
- Concentration gradients — maintained by Na+/K+ ATPase; if pump fails (ischemia, digoxin toxicity) → gradients dissipate → depolarization
Na+/K+ ATPase
| Feature | Detail |
|---|---|
| Stoichiometry | 3 Na+ out, 2 K+ in per ATP hydrolyzed |
| Net effect | Electrogenic — hyperpolarizes membrane by ~5–10 mV |
| Energy cost | Consumes ~40–70% of brain's ATP |
| Inhibitors | Digoxin, ouabain (cardiac glycosides) — bind alpha subunit |
| Clinical | Ischemia → ATP depletion → pump failure → K+ accumulates extracellularly, Na+ accumulates intracellularly → depolarization → excitotoxicity |
Board Pearl
Do not confuse electrogenic with the primary determinant of resting potential. The Na+/K+ ATPase is electrogenic (contributes ~−5 to −10 mV), but the resting membrane potential is primarily set by K+ leak channels and the K+ concentration gradient the pump maintains.
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