# Lecture 1: Cell Membrane Physiology ## Unit 1.6: Physiology Foundations --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the structure and function of the cell membrane 2. Explain the mechanisms of passive transport across membranes 3. Describe active transport mechanisms and their energy requirements 4. Explain the generation and maintenance of membrane potentials 5. Describe the principles of osmosis and tonicity 6. Apply membrane physiology concepts to clinical scenarios --- ## Cell Membrane Structure The cell membrane serves as the critical interface between the cell and its environment, controlling what enters and exits while enabling communication with the external world. The fluid mosaic model, proposed by Singer and Nicolson, describes the membrane as a dynamic structure where proteins float within a sea of phospholipids. Cholesterol molecules intersperse throughout the bilayer, regulating membrane fluidity by preventing fatty acid chains from packing too tightly or moving too freely. Carbohydrate chains attach to proteins and lipids on the extracellular surface, forming the glycocalyx that participates in cell recognition and signaling. The phospholipid bilayer forms the foundation of membrane architecture. Each phospholipid possesses a hydrophilic head group that faces the aqueous environment on either side of the membrane and hydrophobic fatty acid tails that form the interior barrier. The composition of these fatty acid chains affects membrane properties: saturated fatty acids pack tightly and increase rigidity, while unsaturated fatty acids with kinked chains increase fluidity by preventing tight packing. Membrane proteins perform most of the membrane's specific functions. Integral membrane proteins span the entire thickness of the bilayer and include channels, carriers, and receptors that mediate transport and signaling. Peripheral proteins attach to the membrane surface either through interactions with integral proteins or with lipid head groups, serving as enzymes or cytoskeletal anchors. Glycoproteins carry carbohydrate chains that extend into the extracellular space, participating in cell recognition and receptor functions. Membrane fluidity responds to environmental conditions and composition. Temperature affects fluidity directly, with higher temperatures increasing molecular motion. Cholesterol acts as a fluidity buffer, preventing excessive fluidity at high temperatures by restricting phospholipid movement while preventing solidification at low temperatures by disrupting regular packing. The proportion of unsaturated fatty acids in membrane phospholipids also modulates fluidity, with greater unsaturation producing more fluid membranes. Panel A: Phospholipid bilayer structure with hydrophilic heads facing aqueous environments and hydrophobic tails forming the interior barrier. Panel B: Integral membrane proteins spanning the bilayer, including channel proteins with central pores and carrier proteins for transport. Panel C: Peripheral proteins attached to membrane surfaces and cholesterol molecules intercalated between phospholipids regulating fluidity. Panel D: Glycocalyx formation with carbohydrate chains branching from glycoproteins and glycolipids on the extracellular surface. --- ## Passive Transport Passive transport mechanisms move substances across membranes without requiring cellular energy, driven instead by concentration gradients or electrochemical gradients. Simple diffusion represents the most fundamental transport mechanism, involving direct movement of molecules through the lipid bilayer down their concentration gradient. Small, nonpolar molecules such as oxygen, carbon dioxide, and lipid-soluble substances diffuse readily across the membrane. The rate of simple diffusion depends on the concentration gradient, membrane permeability to the substance, and available surface area, relationships formalized in Fick's Law of Diffusion (J = -DA × dC/dx), where flux depends on the diffusion coefficient, area, and concentration gradient. Facilitated diffusion enables polar and charged molecules to cross the membrane with the assistance of transport proteins, still moving down their concentration gradient without energy expenditure. This process exhibits saturation kinetics because the number of transport proteins is limited, and specificity because each transporter handles only particular substrates. Two classes of facilitators exist: channels and carriers. Channels form hydrophilic pores through the membrane, allowing rapid ion passage when open. Carriers bind their substrate and undergo conformational changes to transfer it across the membrane, exemplified by GLUT transporters that move glucose into cells. Ion channels deserve special attention due to their role in electrical signaling. Each channel demonstrates selectivity for particular ions, allowing sodium, potassium, calcium, or chloride to pass while excluding others. Gating mechanisms control channel opening and include voltage-gating, where membrane potential changes trigger conformational changes; ligand-gating, where binding of neurotransmitters or other molecules opens the channel; and mechanical gating, where physical forces such as stretch or pressure cause opening. Ion channels cycle between open, closed, and inactivated states, with the inactivated state representing a temporarily non-responsive condition even when the gating stimulus is present. Panel A: Simple diffusion showing small nonpolar molecules passing directly through the lipid bilayer from high to low concentration. Panel B: Channel-mediated transport with ions flowing through water-filled protein pores down concentration gradients. Panel C: Carrier-mediated facilitated diffusion demonstrating substrate binding, conformational change, and release to cytoplasm. Panel D: Concentration gradient representation showing movement direction from high to low solute concentration. --- ## Active Transport Active transport moves substances against their concentration or electrochemical gradients, requiring energy input to accomplish this thermodynamically unfavorable process. Primary active transport directly couples ATP hydrolysis to transport, using the energy released from breaking the terminal phosphate bond to drive conformational changes in transport proteins. The sodium-potassium ATPase (Na⁺/K⁺-ATPase) exemplifies primary active transport and stands as one of the most important proteins in animal cells. For each ATP molecule hydrolyzed, this pump extrudes three sodium ions from the cell while importing two potassium ions, creating both concentration gradients and a net movement of positive charge that contributes to the membrane potential. The Na⁺/K⁺-ATPase consumes roughly one-third of the ATP produced by a typical cell at rest, reflecting its fundamental importance. Cardiac glycosides such as digoxin inhibit this pump, leading to increased intracellular sodium that secondarily increases intracellular calcium through effects on sodium-calcium exchange, thereby producing the positive inotropic effect exploited therapeutically in heart failure. Other primary active transporters include the calcium ATPase (SERCA in sarcoplasmic reticulum, PMCA in plasma membrane) that maintains the enormous calcium gradient between cytoplasm and both extracellular space and intracellular stores, and the hydrogen-potassium ATPase that acidifies the stomach lumen. Secondary active transport harnesses the energy stored in ion gradients created by primary active transport rather than directly using ATP. Symporters (cotransporters) move two or more substances in the same direction, with the movement of one substance down its gradient providing energy to move another substance against its gradient. The sodium-glucose cotransporter SGLT1 in intestinal epithelial cells uses the sodium gradient to concentrate glucose against its gradient, enabling efficient nutrient absorption. Antiporters (exchangers) move substances in opposite directions. The sodium-calcium exchanger uses the sodium gradient to extrude calcium from cells, while the sodium-hydrogen exchanger helps regulate intracellular pH by extruding protons in exchange for sodium entry. Panel A: Na⁺/K⁺-ATPase primary active transport showing three sodium ions expelled and two potassium ions imported per ATP hydrolyzed. Panel B: Phosphorylation cycle of the pump transitioning between conformational states during ion transport. Panel C: Symporter secondary active transport with sodium and glucose moving together into the cell using the sodium gradient. Panel D: Antiporter secondary active transport showing sodium-calcium exchanger with ions moving in opposite directions. --- ## Osmosis and Tonicity Osmosis describes the movement of water across a semipermeable membrane from regions of lower solute concentration (higher water concentration) to regions of higher solute concentration (lower water concentration). This process continues until equilibrium is reached or until opposing hydrostatic pressure balances the osmotic pressure. Water moves through the membrane via aquaporin channels and to a lesser extent through the lipid bilayer itself. Osmolarity and osmolality quantify solute concentration and its effect on water movement. Osmolarity expresses osmoles per liter of solution (mOsm/L), while osmolality expresses osmoles per kilogram of water (mOsm/kg). Normal plasma osmolality measures approximately 290 mOsm/kg, a value tightly regulated by the hypothalamic-renal axis. Tonicity describes the effective osmolality of a solution relative to the intracellular environment and determines how cells will respond when placed in that solution. Isotonic solutions produce no net water movement, leaving cells unchanged. Hypotonic solutions have lower effective osmolality than the cell interior, causing water to enter cells; continued exposure leads to cell swelling and potentially lysis. Hypertonic solutions have higher effective osmolality, drawing water out of cells and causing shrinkage (crenation in red blood cells). The distinction between effective and ineffective osmoles proves clinically important. Effective osmoles cannot freely cross the cell membrane and therefore contribute to tonicity; sodium and glucose (in the absence of insulin) function as effective osmoles. Ineffective osmoles cross membranes freely and therefore equilibrate without causing sustained water movement; urea exemplifies an ineffective osmole. This explains why uremia (elevated blood urea) increases measured osmolality without causing cell shrinkage, while hypernatremia or hyperglycemia produces both hyperosmolality and hypertonicity. Panel A: Isotonic solution with normal biconcave red blood cell showing equal water movement in both directions and no net change. Panel B: Hypotonic solution causing cell swelling from net water entry, with potential lysis into ghost cells. Panel C: Hypertonic solution causing cell crenation from net water exit with characteristic spiky projections. Panel D: Solute concentration gradients and water molecule movement patterns across the membrane in each condition. --- ## Membrane Potential The resting membrane potential represents the voltage difference across the plasma membrane when a cell is not actively signaling, typically measuring -70 to -90 mV with the interior negative relative to the exterior. This electrical gradient arises from unequal distribution of ions across the membrane combined with selective membrane permeability. Ion distribution across the membrane establishes the chemical gradients that underlie electrical signaling. Potassium concentrations are approximately 140 mM inside and 4 mM outside (35:1 ratio), creating a strong outward chemical gradient. Sodium concentrations reverse this pattern at approximately 14 mM inside and 140 mM outside (1:10 ratio), creating a strong inward gradient. Chloride and calcium also show significant transmembrane gradients, with calcium exhibiting the most extreme difference (approximately 1:20,000 with free cytosolic calcium near 100 nM and extracellular calcium near 2 mM). The equilibrium potential for any ion (calculated using the Nernst equation) represents the membrane potential at which the electrical gradient exactly balances the chemical gradient, producing no net movement of that ion. For potassium, this equilibrium potential is approximately -94 mV; for sodium, approximately +61 mV; for chloride, approximately -89 mV; and for calcium, approximately +123 mV. The resting membrane potential lies closer to the potassium equilibrium potential because the resting membrane is far more permeable to potassium than to other ions. Potassium leak channels remain open at rest, allowing potassium to move toward its equilibrium. The Goldman-Hodgkin-Katz equation extends the Nernst equation to account for multiple ions with different permeabilities, explaining why the resting potential (-70 mV) lies between the sodium and potassium equilibrium potentials but much closer to potassium. The Na⁺/K⁺-ATPase maintains these gradients continuously, preventing dissipation that would occur through ongoing ion movements. Panel A: Ion distribution across the cell membrane showing high intracellular potassium and high extracellular sodium concentrations. Panel B: Na⁺/K⁺-ATPase pump activity maintaining concentration gradients by pumping 3 Na⁺ out and 2 K⁺ in. Panel C: Potassium leak channels allowing K⁺ efflux and generating the resting membrane potential. Panel D: Voltage trace showing resting potential at -70 mV relative to equilibrium potentials for potassium and sodium. --- ## Ion Channels in Detail Voltage-gated ion channels respond to changes in membrane potential by opening or closing, forming the basis for action potentials and other electrical signals. Voltage-gated sodium channels open rapidly when the membrane depolarizes toward threshold, allowing sodium influx that drives the rising phase of the action potential. These channels then inactivate within milliseconds, becoming unresponsive to further depolarization until the membrane repolarizes and they recover. Voltage-gated potassium channels open more slowly during depolarization and remain open longer, producing the potassium efflux that repolarizes the membrane. The different kinetics of these channels—fast sodium activation and inactivation, slower potassium activation—produce the characteristic shape of the action potential. Ligand-gated ion channels open when specific molecules bind to receptor sites on the channel protein. The nicotinic acetylcholine receptor opens when acetylcholine binds, allowing sodium and potassium flux that depolarizes the postsynaptic membrane. GABA-A receptors open a chloride channel when GABA binds, hyperpolarizing the membrane and reducing excitability. NMDA glutamate receptors require both glutamate binding and membrane depolarization (to relieve magnesium block), allowing calcium and sodium entry important for synaptic plasticity and learning. Mechanically-gated channels respond to physical forces such as membrane stretch, pressure, or shear stress. Hair cells in the cochlea use mechanically-gated channels to transduce sound vibrations into electrical signals. Baroreceptors in blood vessel walls detect pressure changes through mechanosensitive channels. Touch receptors in the skin contain mechanically-gated channels that open in response to deformation. Panel A: Voltage-gated sodium channel transitioning through closed, open, and inactivated states in response to membrane potential changes. Panel B: Ligand-gated nicotinic receptor opening upon acetylcholine binding to allow cation flux. Panel C: Mechanically-gated channel in hair cells with tip links transmitting tension to open channels upon stereocilia deflection. Panel D: Comparison of gating mechanisms showing voltage sensors, ligand binding sites, and mechanical linkages for each channel type. --- ## Clinical Applications Cystic fibrosis demonstrates how channel dysfunction produces systemic disease. Mutations in the CFTR gene, which encodes a chloride channel, impair chloride transport across epithelial membranes. Without normal chloride secretion, water fails to follow into secretions, resulting in abnormally thick mucus that obstructs airways, pancreatic ducts, and other passages. Understanding this membrane physiology defect has guided development of therapies targeting the underlying channel dysfunction. Cardiac glycosides such as digoxin exploit membrane transport to produce their therapeutic effects. By inhibiting the Na⁺/K⁺-ATPase, digoxin increases intracellular sodium concentration. This elevation reduces the sodium gradient that drives the sodium-calcium exchanger, leading to less calcium extrusion and higher intracellular calcium. The elevated calcium enhances cardiac contractility, providing benefit in heart failure. However, excessive intracellular calcium causes arrhythmias, explaining digoxin toxicity. Hyperkalemia illustrates the clinical importance of membrane potential. Elevated extracellular potassium reduces the potassium concentration gradient across the membrane, depolarizing the resting membrane potential. This partial depolarization inactivates some sodium channels, reducing excitability and slowing conduction. In cardiac tissue, these effects produce characteristic ECG changes (peaked T waves, widened QRS, sine wave pattern) and can progress to fatal arrhythmias or asystole. Osmotic diuretics such as mannitol apply osmotic principles therapeutically. This non-reabsorbable sugar remains in the renal tubule after glomerular filtration, creating an osmotic gradient that prevents water reabsorption. The resulting diuresis reduces extracellular fluid volume, with applications in cerebral edema and acute kidney injury. Panel A: CFTR chloride channel function in normal epithelium versus cystic fibrosis showing impaired chloride transport and thick mucus accumulation. Panel B: Digoxin mechanism demonstrating Na⁺/K⁺-ATPase inhibition leading to increased intracellular sodium and calcium. Panel C: Hyperkalemia effects on cardiac myocytes showing membrane potential changes and characteristic ECG abnormalities with peaked T waves. Panel D: Mannitol osmotic diuresis in renal tubules preventing water reabsorption through osmotic gradient creation. --- ## Summary The cell membrane is a fluid mosaic of phospholipids, proteins, and cholesterol that serves as a selective barrier and communication interface. Passive transport mechanisms require no energy: simple diffusion moves small nonpolar molecules directly through the lipid bilayer, while facilitated diffusion uses channels and carriers to transport polar and charged substances down their gradients. Active transport requires energy: primary active transport directly uses ATP (exemplified by the Na⁺/K⁺-ATPase that pumps three sodium out and two potassium in), while secondary active transport harnesses ion gradients to move other substances. Osmosis drives water movement from low to high solute concentration, with tonicity determining cell volume responses to extracellular solutions. The resting membrane potential of approximately -70 mV results primarily from potassium permeability and the potassium gradient maintained by the Na⁺/K⁺-ATPase. Ion channels are gated by voltage, ligands, or mechanical stimuli, and their dysfunction underlies numerous diseases. --- ## Key Terms | Term | Definition | |------|------------| | Facilitated diffusion | Protein-mediated transport down concentration gradient requiring no energy | | Na⁺/K⁺-ATPase | Primary active transporter that pumps 3 Na⁺ out and 2 K⁺ in per ATP | | Tonicity | Effective osmolality that determines net water movement and cell volume | | Equilibrium potential | Membrane voltage at which electrochemical gradient is zero for an ion | | Resting membrane potential | Voltage difference across membrane at rest, typically -70 to -90 mV | | Voltage-gated channel | Ion channel that opens or closes based on membrane potential changes | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*