Membrane Structure & Transport

The plasma membrane defines the boundary of the cell and regulates all communication between the intracellular and extracellular environments. Its structure, composition, and transport mechanisms are central to cell physiology and the basis of numerous diseases and drug targets.

The Fluid Mosaic Model

The fluid mosaic model (Singer and Nicolson, 1972) describes the plasma membrane as a dynamic phospholipid bilayer in which proteins are embedded and can move laterally — like icebergs in a lipid sea. The bilayer is amphipathic: phospholipids have hydrophilic head groups (glycerophosphocholine, glycerophosphoethanolamine, etc.) facing aqueous environments on both sides, and hydrophobic fatty acid tails (typically 16–18 carbon) facing inward, forming the 3–4 nm hydrophobic core. This arrangement is thermodynamically stable and is the basis of the membrane's selective permeability.

Membrane phospholipids include phosphatidylcholine (most abundant in the outer leaflet), phosphatidylethanolamine and phosphatidylserine (predominantly inner leaflet), and sphingomyelin (outer leaflet, enriched in lipid rafts). The asymmetric distribution is maintained by flippases (ATP-driven, move PS to inner leaflet), floppases, and scramblases. When PS is exposed on the outer leaflet (as occurs during apoptosis), it signals phagocytes for clearance — the "eat me" signal.

Cholesterol (comprising ~30–40 mol% of the plasma membrane in mammals) intercalates between phospholipids with its rigid sterol ring adjacent to the fatty acid tails. At physiological temperature, it reduces phospholipid mobility and increases membrane order (reducing fluidity). At low temperatures, it prevents gel-phase transition (maintaining fluidity). This temperature-buffering effect keeps membrane fluidity optimal for function. Cholesterol also organises lipid rafts — cholesterol- and sphingolipid-enriched microdomains (~50–200 nm) that concentrate signalling receptors (e.g., GPI-anchored proteins, Src-family kinases) and serve as platforms for signal transduction and pathogen entry (e.g., HIV, cholera toxin via GM1 ganglioside).

Membrane Proteins

Membrane proteins are classified as: integral (intrinsic) — permanently associated with the membrane, requiring detergents or organic solvents for extraction. Transmembrane proteins (type I, II, III, IV; multipass) span the bilayer via α-helical or β-barrel (in bacterial/mitochondrial outer membranes) segments. Lipid-anchored proteins are linked covalently to lipid anchors (GPI on outer leaflet; myristoyl or palmitoyl on inner leaflet). Peripheral (extrinsic) — associated with the membrane surface by ionic interactions or protein-protein contacts; can be removed by high salt or pH changes.

The membrane is asymmetric: the outer leaflet contains glycolipids and glycoproteins (forming the glycocalyx — carbohydrate-rich coat important for cell-cell recognition, blood group antigens, and pathogen binding), while the inner leaflet faces the cytoplasm and contains most signalling lipids (PIP2, PIP3, PS, DAG).

Selective Permeability

The hydrophobic core is an excellent barrier to polar molecules, ions, and large molecules. Permeability rules: small non-polar molecules (O₂, CO₂, N₂, steroid hormones, ethanol, general anaesthetics) diffuse freely by simple diffusion down their concentration gradients. Water crosses slowly by simple diffusion but much faster through aquaporins (AQP1 in RBCs and kidney proximal tubule; AQP2 in kidney collecting duct, regulated by ADH/AVP insertion of vesicles). Small polar uncharged molecules (glycerol, urea) have modest permeability. Ions (Na⁺, K⁺, Ca²⁺, Cl⁻) and charged/large polar molecules (glucose, amino acids, ATP) are essentially impermeant without protein carriers.

Transport Mechanisms

Simple diffusion: Passive, down concentration/electrochemical gradient, no energy, no saturation. Rate proportional to concentration gradient and membrane permeability.

Facilitated diffusion: Passive, down concentration gradient, requires specific membrane protein (channel or uniporter), saturable. Channels: provide aqueous pores, selective by size and charge, can be gated (voltage-gated, ligand-gated, mechanosensitive, constitutively open/leak). GLUT transporters: GLUT1 (ubiquitous, constitutive, low Km, CNS, RBCs); GLUT2 (liver, pancreatic β cells, intestine — high Km sensor); GLUT3 (neurones, high affinity); GLUT4 (skeletal muscle, adipose — insulin-regulated; insulin → PI3K/Akt/AS160 phosphorylation → GLUT4 vesicle translocation to PM).

Primary active transport: Directly uses ATP hydrolysis to move substances against their electrochemical gradient. The Na⁺/K⁺-ATPase (P-type ATPase) exports 3 Na⁺ and imports 2 K⁺ per cycle, maintaining low [Na⁺]ᵢ (~14 mM vs 140 mM extracellular) and high [K⁺]ᵢ (~140 mM vs 5 mM extracellular). This creates the electrochemical gradient that drives secondary active transport and sets the resting membrane potential. Inhibited by cardiac glycosides (digoxin) — raises [Na⁺]ᵢ → reduces NCX activity → raises [Ca²⁺]ᵢ → positive inotropy. The Ca²⁺-ATPase (SERCA) pumps Ca²⁺ into the ER/SR; the H⁺/K⁺-ATPase in gastric parietal cells secretes HCl (inhibited by proton pump inhibitors — omeprazole, lansoprazole).

Secondary active transport: Uses the electrochemical gradient of one ion (usually Na⁺) established by primary active transport to drive uphill movement of another solute. No direct ATP use. Symport (cotransport): both solutes move in the same direction — SGLT1 (Na⁺ + glucose into enterocyte in intestinal brush border; same in kidney proximal tubule; SGLT2 inhibitors — gliflozins — block renal glucose reabsorption → glucosuria → HbA1c reduction in T2DM, plus cardiorenal protective effects). Antiport (countertransport): solutes move in opposite directions — Na⁺/Ca²⁺ exchanger (NCX), Na⁺/H⁺ exchanger (NHE).

Ion Channels

Ion channels provide selective, high-throughput (10⁶–10⁸ ions/sec) pathways for ions. Types: voltage-gated: opened by membrane depolarisation — Nav channels (action potential upstroke), Cav channels (neurotransmitter release, cardiac pacemaking), Kv channels (repolarisation). Ligand-gated: opened by neurotransmitter binding — nAChR (nicotinic acetylcholine receptor, Na⁺/K⁺, fast EPP), GABA-A receptor (Cl⁻, fast IPSP), NMDA receptor (Na⁺/K⁺/Ca²⁺, requires glycine co-agonist and voltage-dependent Mg²⁺ block removal). Mechanosensitive: opened by membrane stretch — Piezo1 (RBC volume regulation, dehydrated hereditary stomatocytosis) and Piezo2 (proprioception). Leak (background): constitutively open, major determinants of resting membrane potential — K2P channels (TASK, TREK families).

Aquaporins: 13 family members (AQP0–12). AQP2 in collecting duct principal cells is regulated by ADH (vasopressin): ADH → V2 receptor (Gs-coupled) → cAMP → PKA → phosphorylation of AQP2 → vesicle insertion into apical membrane → increased water reabsorption. Defects in AQP2 or V2 receptor cause nephrogenic diabetes insipidus.

Vesicular Transport

Endocytosis: clathrin-mediated (receptor-mediated) endocytosis — specific; LDL via LDLR, transferrin via transferrin receptor. Clathrin-coated pits invaginate; dynamin GTPase pinches off vesicle; coat shed; early endosome (pH 6.5) → late endosome (pH 6.0); LDLR recycles to PM (pH-dependent dissociation); LDL delivered to lysosome (pH 4.5) for cholesterol release. Mutations in LDLR cause familial hypercholesterolaemia (FH). Caveolae: flask-shaped invaginations enriched in cholesterol and caveolin-1; involved in transcytosis, lipid homeostasis, and signalling. Macropinocytosis: non-specific, large fluid uptake. Phagocytosis: professional phagocytes (macrophages, neutrophils) engulf particles >0.5 µm; driven by actin polymerisation around a phagocytic cup; FcR or complement receptor mediated.

Exocytosis: constitutive (continuous) or regulated (triggered by Ca²⁺ or other signals). Regulated exocytosis of neurotransmitters: action potential → Cav channel opening → Ca²⁺ influx → SNARE complex formation (synaptobrevin on vesicle with syntaxin + SNAP-25 on PM) → membrane fusion → neurotransmitter release. Botulinum toxin cleaves SNAREs, blocking neurotransmitter release → flaccid paralysis.

Clinical Correlations

Cystic fibrosis: CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-regulated Cl⁻ channel (ABC transporter family) in airway, intestinal, and pancreatic duct epithelium. ΔF508 mutation causes CFTR misfolding → ER retention → ERAD → absent apical Cl⁻ channel → dehydrated airway surface liquid → viscous mucus → impaired mucociliary clearance → chronic Pseudomonas infection → bronchiectasis. CFTR modulators: ivacaftor (potentiator, for Gly551Asp and other gating mutations); lumacaftor/tezacaftor (correctors, partially restore ΔF508 trafficking); elexacaftor (next-generation corrector, ETD triple therapy restores ~50% CFTR function, dramatically improves lung function in ΔF508 patients).

Channelopathies: Long QT syndrome (LQTS) from loss-of-function mutations in IKr (hERG/KCNH2 — LQT2) or gain-of-function in INa (SCN5A — LQT3) → prolonged action potential duration → torsades de pointes → sudden cardiac death. Brugada syndrome (Nav1.5 loss-of-function). Hyperkalaemic periodic paralysis (Nav1.4 gain-of-function in skeletal muscle). Myasthenia gravis (autoimmune destruction of nAChR at NMJ).