Rucete ✏ Lehninger Principles of Biochemistry In a Nutshell
11.3 Solute Transport across Membranes
This chapter explains how cells move nutrients, ions, wastes, and metabolites across membranes using passive diffusion, facilitated transporters, ion channels, and ATP-driven pumps. Transport across membranes is essential for survival, signaling, metabolism, and homeostasis.
Need for Solute Transport
• Every living cell must import raw materials for biosynthesis and energy production.
• Cells must export waste products of metabolism.
• Eukaryotic organelles also maintain different internal concentrations of ions and metabolites, requiring tightly regulated transport across intracellular membranes.
• Only a few small nonpolar molecules can diffuse directly through lipid bilayers.
• Most polar molecules and ions require specific membrane proteins.
• Around 2,000 human genes encode membrane transport proteins.
Major Types of Membrane Transport
• Simple diffusion: direct movement of nonpolar solutes through the membrane down a concentration gradient.
• Facilitated diffusion: passive movement through transport proteins down an electrochemical gradient.
• Primary active transport: movement against a gradient using ATP or another direct energy source.
• Secondary active transport: uphill movement of one solute coupled to downhill movement of another.
• Ion channels: protein pores allowing rapid ion diffusion.
• Ionophores: small molecules that shield ion charge and permit membrane passage.
Concentration Gradient and Membrane Potential
• Solutes spontaneously move from higher concentration to lower concentration until equilibrium is reached.
• Ions are influenced not only by concentration differences but also by electrical charge differences across the membrane.
• Voltage across a membrane is called membrane potential.
• The combined effect of concentration and electrical force is the electrochemical gradient.
• Solutes naturally move toward lower free energy and greater randomness, consistent with the second law of thermodynamics.
Passive vs Active Transport
• Passive transport moves substances down their electrochemical gradient.
• It does not accumulate solute above equilibrium levels.
• Active transport moves substances against a concentration or electrical gradient.
• It requires energy input.
• Active transporters are often called pumps.
• Primary active transport uses ATP or another exergonic reaction directly.
• Secondary active transport uses energy stored in another ion gradient.
Why Lipid Bilayers Block Polar Solutes
• Polar or charged molecules are surrounded by hydration shells of water.
• To cross the membrane directly, they must lose these favorable water interactions.
• They must then pass through the hydrophobic membrane core, which is energetically unfavorable.
• Therefore, pure lipid bilayers are almost impermeable to ions and polar solutes on biologically relevant timescales.
How Transport Proteins Help
• Transporters lower activation energy for membrane crossing.
• They provide hydrophilic pathways lined with polar amino acid side chains.
• They bind specific solutes through many weak noncovalent interactions.
• These interactions compensate for loss of the hydration shell.
• Transporters greatly increase transport rates without chemically changing the solute.
Transporters vs Ion Channels
• Ion channels create aqueous pores across membranes.
• Ions move through open channels extremely rapidly, approaching free diffusion rates.
• Channels may pass tens of millions of ions per second.
• Most channels possess gates controlled by signals such as voltage or ligands.
• Channels are selective but generally not saturable.
• Flow stops when the gate closes or the electrochemical gradient disappears.
• Transporters bind substrates specifically, operate more slowly, and become saturated at high substrate concentration.
• Transporters typically use alternating gates so both sides are never open simultaneously.
Glucose Transport in Erythrocytes: GLUT1
• Red blood cells rely on glucose for energy.
• Blood glucose concentration is usually about 4.5–5 mM.
• Glucose enters erythrocytes via GLUT1.
• GLUT1 increases glucose transport about 50,000-fold over unassisted diffusion.
• Transport follows saturation kinetics similar to enzyme reactions.
• At high glucose concentrations, transport rate approaches Vmax.
• The transport constant Kt is analogous to Km in enzyme kinetics.
• When external glucose equals Kt, transport runs at half-maximal speed.
• Normal blood glucose is near GLUT1’s Kt, allowing effective regulation.
Reversibility of GLUT1
• No chemical bonds are made or broken during glucose transport.
• Therefore, transport is reversible.
• GLUT1 cannot concentrate glucose inside cells above extracellular levels.
• It simply accelerates equilibration.
• Intracellular glucose remains low because entering glucose is rapidly metabolized.
Stereospecificity of GLUT1
• GLUT1 strongly prefers D-glucose.
• Similar sugars such as mannose and galactose bind less efficiently.
• L-glucose is transported very poorly.
• This demonstrates specificity, saturability, and passive transport behavior.
Structure of GLUT1
• GLUT1 is an integral membrane protein with 12 transmembrane helices.
• Many helices are amphipathic, with one polar side and one hydrophobic side.
• Polar surfaces line an internal passage for glucose.
• Hydrophobic surfaces interact with membrane lipids.
• GLUT1 cycles through conformational states:
– outward-open form
– occluded glucose-bound form
– inward-open form
• This alternating-access mechanism transports glucose across the membrane.
Other Human GLUT Transporters
• Humans possess 12 passive glucose transporters with different tissue distributions and properties.
• GLUT1 supplies erythrocytes and helps transport glucose across the blood-brain barrier.
• GLUT1 deficiency can cause seizures, developmental delay, and movement disorders.
• Ketogenic diets may help by providing ketone bodies as alternate brain fuel.
• GLUT2 in liver exports glucose after glycogen breakdown.
• GLUT2 also functions in pancreas, kidney, and intestine.
• GLUT4 is found in muscle, heart, and adipose tissue.
• GLUT4 activity is stimulated by insulin.
GLUT4 and Diabetes
• In resting cells, much GLUT4 is stored in intracellular vesicles.
• Insulin triggers movement of these vesicles to the plasma membrane.
• Vesicle fusion inserts GLUT4 into the membrane.
• This increases glucose uptake into muscle and fat cells.
• When insulin falls, GLUT4 is removed by endocytosis.
• In type 1 diabetes, lack of insulin prevents proper GLUT4 mobilization.
• As a result, glucose uptake falls and blood glucose remains elevated after meals.
Chloride-Bicarbonate Exchanger in Erythrocytes
• Red blood cells also contain an anion exchanger (AE protein).
• It is essential for transporting carbon dioxide from tissues to lungs.
• CO₂ from tissues enters erythrocytes.
• Carbonic anhydrase converts CO₂ + H₂O into bicarbonate (HCO₃⁻) and H⁺.
• Bicarbonate exits into plasma in exchange for chloride.
• This greatly increases blood CO₂ carrying capacity.
• In lungs, bicarbonate reenters RBCs, is reconverted to CO₂, and exhaled.
• The exchanger increases transport rate over a millionfold.
• It is a dimeric protein with 14 membrane-spanning segments.
• One bicarbonate moves one way while one chloride moves the opposite way.
• Net charge movement is zero, so transport is electroneutral.
Uniport, Symport, and Antiport
• Uniport: one solute transported alone (example: GLUT1).
• Symport: two solutes move in the same direction.
• Antiport: two solutes move in opposite directions (example: chloride-bicarbonate exchanger).
• Cotransport refers to transport systems moving two solutes simultaneously.
Why Active Transport Is Necessary
• Cells often need nutrients present externally at very low concentrations.
• Example: E. coli can live in medium with micromolar phosphate while maintaining millimolar intracellular phosphate.
• Cells also pump out ions to maintain signaling and osmotic balance.
• Therefore active transport is essential for life.
Energy Sources for Active Transport
• ATP hydrolysis
• Oxidation reactions
• Sunlight (photosynthesis)
• Flow of another solute down its gradient
Free Energy of Transport
• Moving an uncharged solute uphill depends on concentration ratio.
• Moving an ion also depends on membrane voltage.
• Thus ion pumping may require substantial energy.
• Many cells spend large fractions of their energy budget on ion transport.
• ATP synthesis in mitochondria and chloroplasts is essentially driven by ions flowing down electrochemical gradients.
P-Type ATPases
• P-type ATPases are active transporters that become phosphorylated during their catalytic cycle.
• ATP transfers phosphate to a conserved Asp residue.
• Phosphorylation causes conformational change that moves cations across the membrane.
• Humans encode at least 70 P-type ATPases.
• They usually contain 8 or 10 membrane-spanning segments.
• They are inhibited by vanadate, a phosphate analog.
Major Examples of P-Type ATPases
• Na⁺/K⁺ ATPase in animal cells.
• H⁺ ATPase in plants and fungi.
• SERCA pump in sarcoplasmic/endoplasmic reticulum.
• Plasma membrane Ca²⁺ ATPase.
• Gastric H⁺/K⁺ ATPase in stomach parietal cells.
• Heavy metal pumps exporting toxic ions such as Cu²⁺ and Cd²⁺.
Physiological Importance of P-Type Pumps
• Establish ion gradients across membranes.
• Provide energy for secondary active transport.
• Enable electrical signaling in neurons.
• Maintain low cytosolic Ca²⁺ concentrations.
• Acidify the stomach lumen.
• Detoxify harmful metal ions.
SERCA Pump Mechanism
• SERCA transports Ca²⁺ from cytosol into ER or sarcoplasmic reticulum lumen.
• Each cycle moves two Ca²⁺ ions.
• ATP is converted to ADP + Pi.
• Pump alternates between E1 and E2 conformations.
• In E1, Ca²⁺ binding sites face cytosol.
• Phosphorylation triggers change to E2.
• Ca²⁺ is released into the lumen.
• Dephosphorylation resets the pump.
In a Nutshell
Membrane transport allows cells to import nutrients, remove waste, regulate ion balance, generate electrical signals, and store energy. Passive transport uses gradients, while active transport uses energy to create them. Key systems include GLUT glucose transporters, chloride-bicarbonate exchangers, ion channels, and ATP-driven pumps such as P-type ATPases. Together they are fundamental to cellular life.