6.5 Diffusion, Osmosis & Membrane Transport

The Cell Membrane as a Selective Barrier

The plasma membrane is a phospholipid bilayer with embedded proteins. Its hydrophobic core impedes the passage of charged or polar molecules, so solutes cross by routes that depend on their size, charge, and lipid solubility:

• Lipophilic molecules (O2, CO2, N2, steroid hormones, urea) cross by simple diffusion through the lipid phase.
• Polar or charged molecules require membrane proteins (channels, carriers, pumps) and may move passively (facilitated diffusion) or actively (pumps and cotransporters).
• Macromolecules and particles cross by vesicular transport.

Simple Diffusion

Simple diffusion is the net movement of solute from higher concentration to lower concentration directly through the lipid bilayer. The flux (J) is described by Fick's law: J = -D·A·(ΔC/Δx), where D is the diffusion coefficient (depends on lipid solubility and molecular size), A is membrane area, and ΔC/Δx is the concentration gradient. Key features:

• No energy requirement, no carrier saturation, no competition.
• Rate increases with lipid solubility (partition coefficient) and decreases with molecular size and charge.
• For gases (O2, CO2), rate depends on partial pressure gradients.

Facilitated Diffusion

Facilitated diffusion moves polar or charged solutes down their electrochemical gradient through integral membrane proteins — channels (ion-selective pores gated by voltage, ligands, or mechanics) or carriers (uniporters that undergo conformational change). Examples:

• GLUT1–GLUT5 — glucose uniporters in most cells; GLUT4 in muscle/adipose is insulin-responsive.
• Aquaporins (AQP) — water channels; AQP2 in renal collecting ducts is ADH-regulated.
• Ion channels — K+ leak channels set resting membrane potential; voltage-gated Na+, K+, Ca2+ channels drive action potentials.

Unlike simple diffusion, facilitated diffusion shows carrier specificity, saturation kinetics (Vmax), and competitive inhibition.

Osmosis and Osmolality

Osmosis is the net movement of water across a semipermeable membrane from a region of low solute concentration to one of high solute concentration. The osmotic pressure of a solution is given by van 't Hoff's law: π = nCRT, where n is the number of particles per molecule (osmoles), C is molar concentration, R is the gas constant, and T is temperature.

Osmolality (mOsm/kg water) measures total solute concentration. Plasma osmolality is approximately 290 mOsm/kg, calculated clinically as:

Plasma osmolality ≈ 2[Na+] + [Glucose]/18 + [BUN]/2.8

Tonicity describes the effect of an extracellular solution on cell volume, considering only effective osmoles (solutes that cannot cross the membrane):

• Isotonic — cell volume unchanged (e.g., 0.9% NaCl, 5% dextrose after glucose metabolism).
• Hypotonic — water enters cells; cells swell (e.g., 0.45% NaCl).
• Hypertonic — water leaves cells; cells shrink (e.g., 3% or 5% NaCl, mannitol).

A solution can be isosmotic but hypotonic (e.g., 5% dextrose in water is isosmotic at 278 mOsm/L but becomes hypotonic once glucose is metabolized, leaving free water).

Active Transport

Primary Active Transport

Primary active transport uses ATP directly to move solutes against their electrochemical gradient. Major examples:

• Na+/K+-ATPase — exports 3 Na+ and imports 2 K+ per ATP, establishing the Na+ and K+ gradients and the inside-negative resting potential. Inhibited by cardiac glycosides (ouabain, digoxin), which raise intracellular Na+, reduce Na+/Ca2+ exchange, and increase cardiac contractility.
• Ca2+-ATPase (SERCA in SR, PMCA in plasma membrane) — pumps Ca2+ into SR or out of the cell, lowering cytosolic Ca2+.
• H+/K+-ATPase — gastric parietal cells secrete HCl; also renal α-intercalated cells.
• Ca2+-ATPase in the SR pumps calcium back into the sarcoplasmic reticulum during muscle relaxation.

Secondary Active Transport

Secondary active transport uses the energy stored in the Na+ electrochemical gradient (created by Na+/K+-ATPase) to cotransport another solute against its gradient. Two types:

• Symport (cotransport) — both solutes move in the same direction. Examples: SGLT1 (Na+-glucose, intestinal absorption), SGLT2 (Na+-glucose, renal proximal tubule), Na+-K+-2Cl- (NKCC2) in the thick ascending limb (target of loop diuretics), Na+-I- symporter (NIS) in thyroid follicular cells.
• Antiport (countertransport) — solutes move in opposite directions. Examples: Na+/Ca2+ exchanger (NCX) (3 Na+ in, 1 Ca2+ out — important in cardiac muscle), Na+/H+ exchanger (NHE) in proximal tubule, Cl-/HCO3- exchanger (band 3 protein) in red blood cells.

Glucose Transport Map (Integration)

Vesicular Transport

Large molecules and particles cross membranes in membrane-bound vesicles:

• Endocytosis — plasma membrane invaginates, engulfing extracellular material. Subtypes:
  • Phagocytosis ('cell eating') — uptake of large particles (bacteria, debris) by macrophages, neutrophils.
  • Pinocytosis ('cell drinking') — non-selective uptake of extracellular fluid.
  • Receptor-mediated endocytosis — specific uptake via clathrin-coated pits (e.g., LDL receptor, transferrin receptor). Caveolae-mediated endocytosis uses caveolin in lipid rafts.
• Exocytosis — vesicles fuse with the plasma membrane, releasing contents extracellularly (e.g., neurotransmitter release, hormone secretion, digestive enzyme release).
• Transcytosis — vesicles cross the cell from one surface to the other (e.g., IgA transport across epithelial cells, albumin across capillary endothelium).

Clinical Correlations

• Cholera toxin — enters cells via GM1 ganglioside receptor-mediated endocytosis; activates Gsα permanently, raising cAMP in intestinal epithelium, causing massive secretory diarrhea.
• Cystic fibrosis — mutations in the CFTR chloride channel impair Cl- secretion in lungs, pancreas, and sweat glands.
• SGLT2 inhibitors (empagliflozin) — block renal glucose reabsorption, lowering blood glucose in type 2 diabetes.