Cell Membrane & Transport

The plasma membrane is the selectively permeable interface that defines the cell, controls ionic gradients, and underlies excitability, secretion and absorption. Mastering its structure and transport mechanisms is the conceptual foundation for every organ-system chapter — resting membrane potential, nerve conduction, renal handling and GI absorption all rest on the principles below.

Membrane structure — the fluid mosaic model

Singer & Nicolson's fluid mosaic model (1972) remains the examined framework: a fluid lipid bilayer in which proteins float like icebergs, free to diffuse laterally.

• Lipid bilayer (≈ 50% of mass): phospholipids arranged with hydrophilic phosphate heads facing the aqueous interior/exterior and hydrophobic fatty-acyl tails facing inward. This amphipathic arrangement is the basis of low permeability to water-soluble solutes and ions.
• Phospholipids: phosphatidylcholine and sphingomyelin dominate the outer leaflet; phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol the inner leaflet (asymmetry maintained by flippases/floppases/scramblases).
  • Phosphatidylserine externalisation is the classic "eat-me" signal in apoptosis and a trigger for the coagulation cascade on platelets — a recurring MCQ point.
• Cholesterol: wedged between phospholipids; it decreases fluidity at high (body) temperature and increases fluidity at low temperature, i.e., it acts as a fluidity buffer. It also reduces membrane permeability to small water-soluble molecules.
• Membrane proteins (≈ 50% mass, but >50% by importance):
  • Integral/intrinsic — span the bilayer (transmembrane); function as channels, carriers, pumps, receptors, enzymes. Removable only with detergents.
  • Peripheral/extrinsic — attached to surface or to integral proteins; removable by high salt/pH.
• Carbohydrates (glycocalyx): glycoproteins and glycolipids project externally → cell recognition, blood-group antigens, immune interactions; always on the extracellular surface.

High-yield: The lipid bilayer freely permits lipid-soluble and small uncharged molecules (O₂, CO₂, N₂, alcohols, steroids, urea to a degree); it is virtually impermeable to ions (Na⁺, K⁺, Cl⁻) and large polar molecules, which therefore require proteins.

Determinants of membrane fluidity

Factor	Effect on fluidity
↑ Unsaturated fatty acids (cis double bonds)	↑ Fluidity (kinks prevent packing)
↑ Saturated/long-chain fatty acids	↓ Fluidity
↑ Temperature	↑ Fluidity
Cholesterol (at 37°C)	↓ Fluidity (buffer)

Classification of transport mechanisms

Transport is first divided by energy dependence:

1. Passive (no ATP): simple diffusion, facilitated diffusion, osmosis, ion-channel flux — all move solute down its electrochemical gradient.
2. Active (energy-requiring):
   • Primary active transport — directly uses ATP (pumps).
   • Secondary active transport — uses the gradient (usually Na⁺) created by primary pumps; symport (cotransport, same direction) or antiport (countertransport, opposite direction).
3. Vesicular transport: endocytosis (phagocytosis, pinocytosis, receptor-mediated) and exocytosis — for macromolecules.

High-yield: "Down the gradient = passive (no ATP). Against the gradient = active (needs energy, directly or indirectly)." Facilitated diffusion is passive despite using a carrier.

Simple diffusion and Fick's law

Net flux of a lipid-soluble/uncharged solute is described by Fick's law:

J ∝ (P × A × ΔC) / Δx

where P = permeability coefficient, A = surface area, ΔC = concentration difference, Δx = membrane thickness. Diffusion is therefore faster with greater gradient, larger area, thinner membrane and higher lipid solubility.

• No saturation, no competition, no carrier needed; rate is linear with concentration gradient.
• Gases and steroids cross this way.

Facilitated diffusion vs active transport

Carrier-mediated transport shows three defining kinetic features: saturation (Tmax/Vmax), competition (structural analogues), and specificity.

Feature	Facilitated diffusion	Primary active transport
Direction	Down gradient	Against gradient
Energy (ATP)	Not required	Directly required
Carrier protein	Yes	Yes (pump)
Saturation kinetics	Yes (Vmax)	Yes
Competition	Yes	Yes
Example	GLUT glucose uptake, urea transporter	Na⁺-K⁺ ATPase, Ca²⁺ ATPase, H⁺-K⁺ ATPase

High-yield: Glucose entry into cells via GLUT transporters is facilitated diffusion (passive, down-gradient). Glucose absorption from intestinal lumen and renal tubule via SGLT (Na⁺-glucose cotransporter) is secondary active transport (against gradient, powered by the Na⁺ gradient). Do not confuse the two — a classic distractor.

GLUT transporters worth knowing

• GLUT-1: RBCs, blood-brain barrier (basal uptake).
• GLUT-2: liver, pancreatic β-cell, basolateral gut/renal — high Km, "glucose sensor".
• GLUT-3: neurons (high affinity).
• GLUT-4: insulin-dependent — skeletal muscle and adipose tissue.

Primary active transport — the pumps

Na⁺-K⁺ ATPase (the sodium pump)

The single most examined transporter.

• Pumps 3 Na⁺ out and 2 K⁺ in per ATP hydrolysed → electrogenic (net loss of one positive charge per cycle → contributes a few mV to the resting potential).
• Found in all cell membranes; consumes a large fraction (≈ a third or more in many cells) of basal energy.
• Maintains the high intracellular K⁺, low intracellular Na⁺ that underlies the resting membrane potential, cell volume, and the Na⁺ gradient driving secondary active transport.
• Inhibited by cardiac glycosides (digoxin, ouabain) → ↑ intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchanger activity → ↑ intracellular Ca²⁺ → positive inotropy (mechanism of digoxin).

High-yield: Digoxin inhibits Na⁺-K⁺ ATPase → rise in intracellular Ca²⁺ via the Na⁺-Ca²⁺ exchanger is the molecular basis of its inotropic action. Hypokalaemia potentiates digoxin toxicity (less K⁺ to compete at the pump).

Other primary pumps

• Ca²⁺ ATPase (PMCA, SERCA): extrudes Ca²⁺ / sequesters it into sarcoplasmic reticulum.
• H⁺-K⁺ ATPase: gastric parietal cell apical pump → secretes H⁺; target of proton-pump inhibitors (omeprazole).
• H⁺ ATPase: renal intercalated cells, osteoclast ruffled border.

Secondary active transport

Driven by the Na⁺ electrochemical gradient set up by Na⁺-K⁺ ATPase.

• Symport (cotransport): SGLT-1/2 (Na⁺-glucose), Na⁺-amino-acid cotransporters, Na⁺-K⁺-2Cl⁻ (NKCC2, the loop-diuretic target), Na⁺-Cl⁻ (NCC, thiazide target).
• Antiport (countertransport): Na⁺-H⁺ exchanger (NHE), Na⁺-Ca²⁺ exchanger (NCX), Cl⁻-HCO₃⁻ exchanger (band 3 in RBC = chloride/Hamburger shift).

Flow of intestinal glucose absorption: Lumen → SGLT-1 (apical, Na⁺-glucose symport, secondary active) → enterocyte cytoplasm → GLUT-2 (basolateral, facilitated diffusion) → interstitium/blood; the apical Na⁺ that entered is pumped out basolaterally by → Na⁺-K⁺ ATPase, regenerating the gradient.

Ion channels

Integral proteins forming aqueous pores; allow rapid (10⁶–10⁸ ions/sec), selective, passive ion flux. Far faster than carriers.

• Leak channels: always open (e.g., K⁺ leak channels set resting potential).
• Voltage-gated: open in response to membrane potential change (Na⁺, K⁺, Ca²⁺ channels of action potentials).
• Ligand-gated (ionotropic): open on binding a chemical (nicotinic ACh receptor, GABA-A → Cl⁻, NMDA).
• Mechanically gated: stretch/pressure (hair cells, baroreceptors).

High-yield: Channels show selectivity and gating but not classic saturation kinetics like carriers; they conduct far faster than carrier proteins because there is no conformational cycling per ion.

Osmosis, osmolarity and tonicity

• Osmosis: net diffusion of water across a semipermeable membrane from low to high solute concentration (low to high osmolarity).
• Osmotic pressure: pressure needed to oppose osmosis; given by van't Hoff: π = nCRT (n = number of dissociated particles, C = molar concentration). NaCl → n = 2; glucose → n = 1.
• Osmolarity (osmoles/L solution) vs osmolality (osmoles/kg water). Plasma osmolality ≈ 285–295 mOsm/kg.
• Estimated plasma osmolality = 2[Na⁺] + glucose/18 + BUN/2.8 (mg/dL units). An elevated osmolar gap suggests unmeasured osmoles (methanol, ethylene glycol, ethanol, mannitol).

Tonicity vs osmolarity

Tonicity depends only on non-penetrating (effective) solutes and predicts cell volume change; osmolarity counts all solutes.

Solution	Osmolarity	Effect on RBC
Isotonic (0.9% NaCl, 5% dextrose initially)	≈ plasma	No change
Hypotonic (0.45% NaCl, water)	< plasma effective	Cell swells → haemolysis
Hypertonic (3% NaCl, mannitol)	> plasma effective	Cell shrinks → crenation

High-yield: Urea and isotonic urea solutions are iso-osmotic but hypotonic — urea penetrates the membrane, so it does not hold water out; cells in iso-osmotic urea still swell and lyse. This penetrating-solute trap is a favourite MCQ.

Gibbs-Donnan equilibrium

When one side of a membrane contains a non-diffusible charged macromolecule (e.g., plasma proteins, intracellular proteins), the distribution of diffusible ions becomes unequal at equilibrium.

Key consequences (memorise the pattern):

1. The compartment with the impermeant anion (protein⁻) has more total diffusible ions and slightly more cations, hence higher osmotic activity → tendency to draw water in.
2. Product of diffusible ion pairs is equal on both sides: [Na⁺]₁ × [Cl⁻]₁ = [Na⁺]₂ × [Cl⁻]₂.
3. Electrical neutrality holds within each compartment, but a small membrane potential (Donnan potential) develops.
4. Physiological relevance: contributes to the slight excess of intravascular ion content (plasma proteins), and the cell would tend to swell from this effect — counteracted by the Na⁺-K⁺ ATPase pumping Na⁺ out (the "pump-leak" hypothesis for cell volume regulation).

High-yield: At Gibbs-Donnan equilibrium the side with the non-diffusible anion holds more total osmotically active particles → without active pumping the cell would swell and burst. Na⁺-K⁺ ATPase counters this by treating Na⁺ as functionally impermeant.

Vesicular transport

• Endocytosis: phagocytosis ("cell eating", large particles, e.g., neutrophils/macrophages), pinocytosis ("cell drinking", fluid), receptor-mediated endocytosis via clathrin-coated pits (LDL uptake — defective LDL receptor → familial hypercholesterolaemia).
• Exocytosis: vesicle fusion releasing contents (neurotransmitters, hormones); Ca²⁺-dependent and mediated by SNARE proteins (synaptobrevin, syntaxin, SNAP-25). Botulinum and tetanus toxins cleave SNAREs, blocking neurotransmitter release.
• Transcytosis: endocytosis on one face, exocytosis on the other (capillary endothelium).

Membrane potential — quick link

The Na⁺-K⁺ ATPase plus selective K⁺ leak give a resting membrane potential ≈ –70 mV (neurons), close to the K⁺ equilibrium potential.

• Nernst equation (single ion): E_ion = (61/z) × log([out]/[in]) at 37°C.
• Goldman-Hodgkin-Katz equation: weighted by permeability of all permeant ions; at rest membrane is most permeable to K⁺, so resting potential lies nearest E_K.

High-yield: Resting potential is dominated by K⁺ permeability; depolarisation in the action potential upstroke is due to a sudden rise in Na⁺ permeability (voltage-gated Na⁺ channels).

Clinically relevant transport defects

• Cystic fibrosis: CFTR (cAMP-regulated Cl⁻ channel) mutation → thick secretions; ΔF508 commonest.
• Cystinuria: defective dibasic amino-acid (COLA: Cystine, Ornithine, Lysine, Arginine) transporter → cystine renal stones.
• Hartnup disease: neutral amino-acid (tryptophan) transporter defect → pellagra-like rash, cerebellar ataxia.
• Bartter syndrome: NKCC2 loss (mimics loop diuretic). Gitelman syndrome: NCC loss (mimics thiazide).
• Familial hypercholesterolaemia: defective LDL-receptor-mediated endocytosis.

Recently asked / exam angle

• Glucose entry into cell is by which transport? → Facilitated diffusion (GLUT); intestinal/renal absorption is secondary active (SGLT).
• Na⁺-K⁺ ATPase pumps how many ions? → 3 Na⁺ out, 2 K⁺ in; electrogenic; digoxin/ouabain inhibit.
• Iso-osmotic but hypotonic solution? → Urea (penetrating solute).
• Mechanism of digoxin inotropy? → Na⁺-K⁺ ATPase inhibition → ↑ intracellular Ca²⁺ via Na⁺-Ca²⁺ exchanger.
• Which leaflet has phosphatidylserine and what is its role? → Inner leaflet; externalised in apoptosis ("eat-me") and coagulation.
• Gibbs-Donnan: which side has more particles? → Side with non-diffusible protein anion.
• Cholesterol effect on fluidity at body temperature? → Decreases fluidity (buffer).
• Clathrin-coated pit / receptor-mediated endocytosis example? → LDL uptake.
• SNARE-cleaving toxin? → Botulinum/tetanus toxin blocks exocytosis.
• Plasma osmolality normal range? → 285–295 mOsm/kg.

Mnemonics

• Na⁺-K⁺ pump stoichiometry: "3 out, 2 in" — "3 sodium leave, 2 potassium enter."
• Cystinuria substrates: COLA (Cystine, Ornithine, Lysine, Arginine).
• GLUT-4 = "4 the muscle and fat, insulin-dependent."

Rapid revision

• Fluid mosaic model: lipid bilayer + floating proteins; carbohydrates only on the outer surface.
• Cholesterol is a fluidity buffer; unsaturated cis fatty acids increase fluidity.
• Lipid-soluble and small uncharged molecules cross by simple diffusion (Fick's law, no carrier, no saturation).
• Facilitated diffusion = passive, carrier, saturable, down-gradient (GLUT).
• Secondary active transport uses the Na⁺ gradient: SGLT (symport), Na⁺-Ca²⁺ exchanger (antiport).
• Na⁺-K⁺ ATPase: 3 Na⁺ out / 2 K⁺ in, electrogenic, inhibited by digoxin & ouabain.
• PPIs block the gastric H⁺-K⁺ ATPase; loop diuretics block NKCC2; thiazides block NCC.
• Tonicity depends on non-penetrating solutes; urea solution is iso-osmotic but hypotonic → haemolysis.
• van't Hoff: π = nCRT; NaCl gives n = 2, glucose n = 1.
• Gibbs-Donnan: non-diffusible anion side has more total ions; product of diffusible ions equal both sides; pump-leak prevents cell swelling.
• Resting potential nearest E_K (K⁺ dominant permeability); action-potential upstroke from Na⁺ influx.
• Exocytosis is Ca²⁺- and SNARE-dependent; botulinum/tetanus toxins cleave SNAREs.