The Lipid Bilayer and Ion Channels
Hydrophobic Self-Assembly, Potassium Selectivity Filters, and the Resting Membrane Voltage
Evert Gorter and François Grendel extracted the lipids from a known count of red blood cells in 1925 and spread them across a Langmuir water trough. Compressing the floating film to a single molecular layer covered twice the surface area of the intact cells. That two-to-one ratio proved the plasma membrane is a two-molecule-thick lipid bilayer.
Phospholipid bilayers do not hold together through covalent bonds between their hydrocarbon tails. Instead, they self-assemble in water via the hydrophobic effect. Expelling oily carbon chains from liquid water frees neighboring water molecules from rigid hydrogen-bonded cages, increasing solvent entropy and locking the two membrane leaflets together thermodynamically.
A single phospholipid molecule diffuses laterally across a cell membrane at two micrometers per second, swapping places with adjacent lipids ten million times each second. Yet that same molecule flips spontaneously between leaflets less than once a day. Dragging its polar headgroup through the oily core costs $80\text{ kJ/mol}$ without flippase enzymes.
The insulating hydrocarbon core of a plasma membrane is only 3.5 to 4 nanometers thick. A resting potential of $-70\text{ mV}$ across that thin barrier creates an intense voltage gradient. Dividing $0.07\text{ V}$ by $3.5\text{ nm}$ yields an electric field of $20\text{ million V/m}$—nearly seven times the breakdown field that triggers lightning in air.
Every biological membrane acts as a parallel-plate capacitor with a specific capacitance of roughly $1\text{ }\mu\text{F/cm}^2$. Charging a spherical cell ten micrometers wide to $-70\text{ mV}$ requires moving only 1.4 million potassium ions across the bilayer. That tiny charge shift alters the cell's 44 billion internal potassium ions by less than one part in thirty thousand.
Pure phospholipid bilayers are ten billion times less permeable to sodium and potassium ions than to water molecules. Water dipoles cling tightly to dissolved ions in solution. Stripping that hydration shell off a bare ion to enter a low-dielectric hydrocarbon oil ($\varepsilon \approx 2$) imposes an electrostatic Born energy barrier of $150\text{ kJ/mol}$.
Roderick MacKinnon solved the $3.2\text{-\AA}$ X-ray crystal structure of the bacterial KcsA potassium channel in 1998 to explain a classic biophysical paradox. The open pore conducts larger potassium ions ($1.33\text{-\AA}$ radius) at 100 million ions per second. Yet it rejects smaller sodium ions ($0.95\text{-\AA}$ radius) by a factor of ten thousand to one.
Inside the KcsA selectivity filter, four conserved TVGYG peptide loops point sixteen backbone carbonyl oxygens inward into a narrow tunnel. Those rigid oxygen rings mimic the exact eight-water hydration shell of a potassium ion, shedding its water penalty free of charge. A smaller sodium ion cannot touch both oxygen walls simultaneously and stays outside.
How can a selectivity filter bind potassium tightly enough to exclude sodium while still passing $10^8$ ions per second? Two to three potassium ions occupy the four sequential binding sites inside the filter at the same time. Mutual electrostatic repulsion between those closely packed positive charges knocks the leading ion out into the extracellular fluid.
Erwin Neher and Bert Sakmann pressed a fire-polished glass micropipette with a one-micrometer tip against a frog muscle fiber in 1976. By applying gentle suction, they achieved a tight gigaohm electrical seal against the membrane. Their patch-clamp amplifier resolved square two-picoampere current steps, catching a single acetylcholine receptor channel snapping open and shut.
Voltage-gated sodium and potassium channels detect membrane depolarization through four transmembrane S4 alpha helices. Every third residue along each S4 helix is a positively charged arginine or lysine. When interior voltage becomes less negative, the $20\text{-MV/m}$ electric field relaxes its inward pull and lets the S4 paddles screw outward by 10 angstroms.
To keep a firing nerve axon from locking into permanent excitation, voltage-gated sodium channels shut off automatically within one millisecond of opening. Clay Armstrong and Francisco Bezanilla proved in 1977 that a tethered cytoplasmic peptide loop acts as a hinged plug. It swings into the open inner pore to block ion flow until the membrane repolarizes.