Difficulty: Intermediate | Prerequisites: Lessons 1–3 notes (protein structure, enzyme kinetics, ATP and energy carriers)
Lessons 7 through 9 cover everything about biological membranes: what they are made of, how they are organised, and how molecules get across them. Lesson 7 deals with membrane lipids and proteins, including the red blood cell cytoskeleton. Lesson 8 introduces channels, transporters, and the principles of passive and active transport, with clinical applications in neuromuscular signalling and glucose absorption. Lesson 9 covers the ATP-powered pumps (P-type, F-type, V-type, ABC superfamily), the sodium-potassium pump, action potentials, and cystic fibrosis. You need the protein structure concepts from Lesson 3 and the ATP/energy carrier material from Lesson 2 to follow the transport mechanisms.
Cell membranes are asymmetric phospholipid bilayers studded with proteins that control what enters and exits the cell. Small uncharged molecules diffuse freely, but ions, glucose, and other polar solutes require channels (fast, passive, gated) or transporters (slower, conformational changes). Moving molecules against their gradient requires active transport: either ATP-driven pumps (primary) or coupling to a favourable ion gradient (secondary). Disruption of these systems underlies diseases from hereditary spherocytosis to cystic fibrosis.
Phospholipid
The most abundant type of lipid in cell membranes. Two classes: glycerophospholipids and sphingolipids (which have a sphingosine backbone). Each has a hydrophilic head and two hydrophobic tails.
Glycolipid
A sphingosine-based lipid with a sugar headgroup instead of a phosphate. Found on the outer leaflet of the plasma membrane. Think of it as a sphingolipid with a sugar hat instead of a phosphate hat.
Cholesterol
A membrane lipid that sits between phospholipids and regulates membrane fluidity. Cannot form a bilayer on its own.
Membrane fluidity
The degree to which lipids and proteins can move within the bilayer. Regulated by acyl chain saturation (more unsaturated = more fluid) and cholesterol content.
Lipid raft (microdomain)
A region of the membrane enriched in cholesterol, sphingolipids, and specific proteins. Associated with receptor signalling, membrane internalisation, and cell adhesion.
Integral (intrinsic) membrane protein
A protein embedded in the lipid bilayer. Can be single-pass (one transmembrane α helix), multipass (multiple α helices or a β barrel), or leaflet-associated (does not span the full bilayer).
Peripheral (extrinsic) membrane protein
A protein non-covalently attached to the membrane surface, typically by binding to an integral protein.
GPI anchor
A glycosylphosphatidylinositol linkage that tethers a protein to the outer leaflet of the membrane. Added in the rough ER.
Glycocalyx
A carbohydrate-rich protective layer on the extracellular surface of certain cell types, formed by sugar modifications on membrane proteins and lipids.
Spectrin
A long, thin, flexible protein (α and β forms) that forms the mesh of the red blood cell membrane cytoskeleton, giving the cell its biconcave shape.
Hereditary spherocytosis
A group of hemolytic anemias caused by mutations in RBC cytoskeletal proteins (ankyrin, spectrin α/β, band 3, protein 4.2). Red blood cells lose their biconcave shape and become spherical, leading to premature lysis.
Channel
A transmembrane protein that forms an aqueous pore for ions or water. Fastest transport rate (no conformational change while open). Passive transport only. Gated: voltage-gated, ligand-gated, or mechanically gated.
Transporter (carrier)
A transmembrane protein that moves solutes by cycling between outward-facing and inward-facing conformations. Slower than channels because each transport event involves a conformational change.
Uniport
Transport of a single solute down its concentration gradient. Always passive.
Symport
Coupled transport of two solutes in the same direction. One moves down its gradient, driving the other against its gradient.
Antiport
Coupled transport of two solutes in opposite directions. One moves down its gradient, driving the other against its gradient.
Primary active transport
Transport powered directly by ATP hydrolysis (ATP-driven pumps).
Secondary active transport
Transport powered by an existing ion gradient (which was itself established by primary active transport). Uses coupled transporters (symport or antiport).
Na⁺/K⁺ ATPase (sodium-potassium pump)
A P-type pump that exports 3 Na⁺ and imports 2 K⁺ per ATP hydrolysed. Establishes the Na⁺ and K⁺ gradients across the plasma membrane. Uses roughly one-third of a typical cell's ATP (one-half in neurons).
Resting membrane potential
The voltage difference across the plasma membrane at rest, approximately −70 mV (inside negative). Primarily set by K⁺ leak channels allowing K⁺ to flow out until its electrochemical gradient reaches equilibrium (~−59 mV), with a minor contribution from the electrogenic Na⁺/K⁺ ATPase.
Action potential
A rapid, transient reversal of membrane polarity (from −70 mV to roughly +50 mV) mediated by voltage-gated Na⁺ channels. Propagates unidirectionally along excitable cells (neurons, muscle cells) because Na⁺ channels enter an inactivated state after opening (refractory period).
P-type pump
An ATP-driven pump that is phosphorylated on its α subunit during the transport cycle. Substrates: ions only (H⁺, Na⁺, K⁺, Ca²⁺). Mechanism: E1–E2 conformational change.
SERCA Ca²⁺ ATPase
A P-type pump in the sarcoplasmic reticulum membrane that pumps 2 Ca²⁺ ions from the cytoplasm into the SR lumen per ATP hydrolysed. Essential for muscle relaxation.
F-type pump (ATP synthase)
A mitochondrial complex where H⁺ flow through the F₀ sector drives rotation of the c-subunit ring, which transmits rotary motion through the γ subunit to the F₁ sector, causing conformational changes in α and β subunits that synthesise and release ATP. In humans, operates in the direction of ATP synthesis (not proton pumping).
V-type pump (vacuolar ATPase)
An ATP-driven proton pump that acidifies lysosomes and endosomes. Uses ATP hydrolysis to pump H⁺ into the lumen. Cl⁻ channels accompany V-type pumps to balance the charge.
ABC transporter
An ATP binding cassette transporter with 2 transmembrane (T) domains and 2 cytosolic ATP-binding (A) domains. Transports a wide range of substrates (ions, sugars, amino acids, lipids, peptides). Not phosphorylated during transport.
MDR transporter (P-glycoprotein)
A multidrug resistance ABC transporter that exports drugs and cytotoxic molecules from cells. Broad specificity for small, hydrophobic molecules. Contributes to drug resistance in certain cancers.
CFTR
Cystic fibrosis transmembrane conductance regulator. An ABC-family protein that functions as a Cl⁻ channel (not a pump) in the apical membrane of airway epithelial cells. Activated by phosphorylation of its R domain and ATP hydrolysis. Also indirectly regulates Na⁺ transport.
Cystic fibrosis
A genetic disease caused by loss-of-function mutations in CFTR. Absent or dysfunctional Cl⁻ channel → abnormal ion and water transport → thick, dehydrated mucus in airways → impaired ciliary clearance → chronic bacterial infection, inflammation, and tissue damage. Affects lungs, pancreas, liver, GI system, and urogenital system.
Membrane Lipid Classes
Storage lipids (neutral): triacylglycerols
Membrane lipids (polar): phospholipids are the most abundant
Glycerophospholipids: glycerol backbone
Sphingolipids: sphingosine backbone
Glycolipids: sphingosine + monosaccharide or oligosaccharide (no phosphate); present on the outer leaflet
Cerebroside: sphingosine + monosaccharide (no charge)
Ganglioside: sphingosine + oligosaccharide + sialic acid (NANA)
Cholesterol: wedges between phospholipids, regulates fluidity; cannot form a bilayer alone
Lipid Organisation and Movement
Cone-shaped lipids form micelles; cylinder-shaped lipids form bilayers
Lipid movements within the bilayer: lateral diffusion (fast, favourable), acyl chain flexion, rotation
Flip-flop (transverse movement) is energetically unfavourable because the polar headgroup must cross the hydrophobic core
Flippase proteins catalyse regulated flip-flop to maintain leaflet asymmetry
Bilayer thickness is regulated by acyl chain saturation and cholesterol content
Plasma Membrane Asymmetry
Outer leaflet: glycolipids
Inner leaflet: phosphatidylserine (PS, net negative charge) and inositol lipids (PI, PIP, PIP2)
Asymmetry maintained by low rates of spontaneous flip-flop and specific flippase proteins
Membrane Microdomains (Lipid Rafts)
Lateral separation of lipids and proteins produces microdomains enriched in cholesterol and sphingolipids
Functions: receptor signalling, membrane internalisation, cell–cell and cell–matrix adhesion
Membrane Protein Classes
Integral (intrinsic):
Type 1: single-pass with one transmembrane α helix
Type 2: multipass with multiple transmembrane α helices
Type 3: multipass with rolled β barrel
Type 4: leaflet-associated, does not span the full bilayer
Anchored:
Type 5: protein with fatty acid or prenyl group in one leaflet
Type 6: protein with GPI anchor
Peripheral (extrinsic):
Types 7 and 8: non-covalently attached to integral proteins
Transmembrane Domain Features
Most transmembrane domains are α helices, typically 20–25 amino acids long, with no charged side chains
Extracellular domains may be glycosylated or stabilised by disulfide bonds
Proteins on one side of the membrane can be anchored by fatty acid chains, prenyl (farnesyl) groups, or GPI anchors
Membrane Carbohydrates
Attached to proteins or lipids as modifications (not embedded in the hydrophobic core)
All located on the ectoplasmic (extracellular) face, added in the secretory pathway
Some cells form a glycocalyx: a protective carbohydrate-rich layer
Membrane Protein and Lipid Mobility
Most membrane components are mobile: lateral diffusion and rotational movement are common
Flip-flop across the bilayer is rare for both proteins and lipids
Mobility can be restricted by self-association, interactions with extracellular or intracellular molecules, or interactions with proteins on neighbouring cells
Epithelial cells: tight junctions prevent movement of membrane components between apical and basolateral surfaces
Red Blood Cell Membrane Cytoskeleton
RBCs have a biconcave shape that maximises surface area to volume ratio for gas exchange
Shape depends on the membrane-associated cytoskeleton:
Spectrins (α and β): long, flexible proteins forming a mesh
Junctional complexes with short actin filaments bind spectrin tetramer ends
Glycophorin: membrane glycoprotein binding junctional complexes
Band 3: transmembrane protein binding ankyrin (which binds spectrin tetramers); also functions as an anion antiporter
RBCs are primarily filled with haemoglobin, glycolytic enzymes, and carbonic anhydrase
Hereditary Spherocytosis (Clinical Application)
Mutations in cytoskeletal genes (ANK1/ankyrin, SPTB/spectrin β, SPTA1/spectrin α, SLC4A1/band 3, EPB42/protein 4.2) disrupt the membrane skeleton
RBCs become spherical, losing their biconcave shape
Hemolytic anaemia: RBCs are destroyed faster than bone marrow can replace them
Can be asymptomatic if mild
Ion Gradients Across the Plasma Membrane
Na⁺: higher outside the cell
K⁺: higher inside the cell
Cl⁻: higher outside the cell
Ca²⁺: very low inside the cell
These gradients produce a resting membrane potential of approximately −70 mV
Channels
Three conformational states: open, closed, inactivated
Fastest transport rate of any transport mechanism (no conformational changes while open)
Passive transport only (down the electrochemical gradient)
Channel selectivity: determined by interactions between ions and amino acid side chains in the selectivity filter
K⁺ (the selected ion in K⁺ channels): many favourable interactions with the selectivity filter → low activation energy
Na⁺ (wrong ion in K⁺ channels): poor interactions → high activation energy → excluded
Channel Gating
Voltage-gated: opens/closes in response to changes in membrane potential
Ligand-gated: opens/closes in response to binding of an extracellular or intracellular ligand
Mechanically gated: opens/closes in response to mechanical stress
Resting state varies by channel (some default open, others default closed)
Transporters
Cycle between outward-facing and inward-facing conformations
Move solute down its concentration gradient; direction reverses if gradient reverses
Slower than channels because each transport event requires a conformational change
Transport Modes
Uniport: one solute, down its gradient, always passive
Coupled transport (cotransport): movement of one ion/molecule is coupled to movement of another
Symport: both solutes move in the same direction
Antiport: solutes move in opposite directions
Active Transport
Primary active transport: ATP-driven pump (ATPase hydrolyses ATP → conformational change moves ion across membrane)
Secondary active transport: energy from an existing ion gradient (established by primary active transport) drives transport of another solute against its gradient via a coupled transporter
Acetylcholine Receptor Channel
Ligand-gated channel that binds acetylcholine (neurotransmitter)
Located in the sarcolemma of skeletal muscle at the neuromuscular junction
Neuromuscular Junction Signalling (Clinical Application)
Step 1: Voltage-gated Ca²⁺ channel in nerve terminal triggers acetylcholine secretion into synapse
Step 2: Acetylcholine binds receptor → Na⁺ flows in → sarcolemma depolarises
Step 3: Voltage-gated Na⁺ channel propagates action potential across sarcolemma into T-tubule
Step 4: Voltage-gated Ca²⁺ channel in T-tubule interacts with Ca²⁺ channel in sarcoplasmic reticulum
Step 5: Ca²⁺ released from SR → muscle contraction
Aquaporins
Water channel proteins lined with amino acid side chains that interact with individual H₂O molecules
Water moves in single file to prevent proton hopping (H-bonded water can conduct protons rapidly; single-file movement blocks this)
Anion Antiporters and pH Regulation
Anion exchanger 1 (AE1, band 3): antiporter of Cl⁻ and HCO₃⁻; most abundant transmembrane protein in RBCs
To raise intracellular pH: Na⁺/H⁺ antiporter exports H⁺; Na⁺HCO₃⁻/Cl⁻ cotransporter imports HCO₃⁻
To lower intracellular pH: Cl⁻/HCO₃⁻ antiporter exports HCO₃⁻
Chloride Shift in Gas Transport
In systemic capillaries: CO₂ diffuses into RBC → carbonic anhydrase converts CO₂ + H₂O → HCO₃⁻ + H⁺ → AE1 exports HCO₃⁻ and imports Cl⁻ (chloride shift) → ~80% of CO₂ is carried in plasma as HCO₃⁻
In lung capillaries: the reverse → HCO₃⁻ re-enters the RBC → converted back to CO₂ → CO₂ diffuses out and is exhaled
Glucose Transporters
Facilitative glucose transporters (GLUTs): passive uniport, move glucose down its gradient
GLUT1: low Kₘ, high affinity, ubiquitous, reaches Vₘₐₓ quickly
GLUT2: high Kₘ, low affinity, found in liver, intestine, kidney
GLUT4: insulin-regulated, found in skeletal muscle and adipose tissue
Na⁺-glucose cotransporters (SGLTs): secondary active transport (symport)
SGLT1: high affinity, low capacity, intestine and renal tubules
SGLT2: low affinity, high capacity, renal tubules (reabsorbs ~90% of glucose in kidney)
GLUT1 Conformational Change Mechanism
Step 1: glucose binds outward-facing conformation
Step 2: conformational change (requires bound glucose)
Step 3: glucose released from inward-facing conformation
Step 4: return to outward-facing conformation (slow, rate-limiting step)
GLUT4 and Insulin
Insulin increases the Vₘₐₓ of GLUT4-mediated glucose transport by increasing the number of GLUT4 transporters in the plasma membrane
Mechanism: insulin signalling stimulates fusion of recycling endosomes (containing stored GLUT4) with the plasma membrane
This process is reversible: when insulin drops, GLUT4 is endocytosed back into storage vesicles
Sodium-Glucose Symport (SGLT)
2 Na⁺ + 1 glucose enter the cell together (symport)
Na⁺ moves down its gradient (established by Na⁺/K⁺ ATPase), driving glucose uptake against its gradient
Conformational change requires binding of both Na⁺ and glucose
Na⁺ gradient imposes unidirectionality
Epithelial Glucose Transport (Clinical Application)
Apical side: Na⁺/glucose symporter (SGLT) moves glucose into the cell using the Na⁺ gradient
Basal side: Na⁺/K⁺ ATPase maintains the Na⁺ gradient; GLUT2 uniporter moves accumulated glucose out of the cell and into blood
SGLT2 Inhibitors (Clinical Application)
SGLT2 reabsorbs ~90% of glucose filtered by the kidney
Inhibiting SGLT2 allows more glucose to be excreted in urine (does not affect dietary glucose absorption via SGLT1 in the intestine)
Used to treat hyperglycaemia / type 2 diabetes by lowering blood glucose levels
ATP-Powered Pumps: General Features
Unidirectional (energy input commits the direction)
Slower than channels and transporters
Three main types: P-type, F-type and V-type, ABC superfamily
P-Type Pumps
Substrates: ions only (H⁺, Na⁺, K⁺, Ca²⁺)
α subunit: large, transmembrane, contains the ion pathway and a cytosolic domain that binds ATP and is phosphorylated
β subunit: small, transmembrane, regulatory
Mechanism: E1 ↔ E2 conformational change in the α subunit, driven by phosphorylation/dephosphorylation
SERCA Ca²⁺ ATPase
Pumps 2 Ca²⁺ from cytoplasm into the SR lumen per ATP hydrolysed
E1 conformation: high-affinity Ca²⁺ binding sites face cytosol → Ca²⁺ and ATP bind → ATP hydrolysed → α subunit phosphorylated
E2 conformation: low-affinity sites face SR lumen → Ca²⁺ released → dephosphorylation returns pump to E1
Na⁺/K⁺ ATPase
3 Na⁺ out, 2 K⁺ in, 1 ATP per cycle
Consumes ~⅓ of total cellular ATP in most cells; ~½ in neurons
Establishes both the Na⁺ concentration gradient and the electric potential across the plasma membrane
The Na⁺ gradient is used to power secondary active transport (symport and antiport)
Resting Membrane Potential
K⁺ leak channels allow K⁺ to flow out of the cell until its electrochemical gradient reaches zero (~−59 mV)
The Na⁺/K⁺ ATPase is electrogenic (3 positive charges out per 2 in), contributing a minor additional negative shift
Combined result: resting potential of approximately −70 mV
Action Potentials
Occur in excitable cells: neurons, muscle cells, Purkinje fibres
Requirements: resting membrane potential, voltage-gated Na⁺ channels, a stimulus
Depolarisation: stimulus opens voltage-gated Na⁺ channels → Na⁺ rushes in → membrane potential rises from −70 mV to ~+50 mV
Repolarisation: Na⁺ channels inactivate, K⁺ leak channels restore K⁺ equilibrium, Na⁺/K⁺ ATPase restores ion gradients
Refractory period: time during which Na⁺ channels are inactivated and cannot reopen
Propagation is unidirectional because inactivated Na⁺ channels behind the wavefront cannot re-fire
F-Type Pumps (ATP Synthase)
Substrate: H⁺ only
F₁ sector: catalytic, cytosol-facing, contains multiple subunits (not phosphorylated)
F₀ sector: transmembrane, contains the c-subunit ring
Mechanism in humans: H⁺ flows through F₀, rotating the c-ring → γ subunit transmits rotation to F₁ → conformational changes in α and β subunits drive ATP synthesis and release
Operates in the direction of ATP synthesis in human mitochondria (not proton pumping)
V-Type Pumps (Vacuolar ATPase)
Substrate: H⁺ only
V₁ sector: catalytic, cytosol-facing (like F₁)
V₀ sector: transmembrane (like F₀)
Mechanism: proton pumping only (the reverse of F-type); no ATP synthesis
Function: acidifies lysosomes and endosomes
Cl⁻ channels accompany V-type ATPases to balance the charge that accumulates from proton import
ABC Transporter Superfamily
Substrates: ions, sugars, amino acids, lipids, peptides (broadest substrate range)
Structure: 2 transmembrane (T) domains + 2 ATP-binding (A) domains; can be 4 separate proteins or 1 multidomain protein
Not phosphorylated during transport
A domains face cytosol and carry out ATP hydrolysis
T domains form the transmembrane pathway; mechanism accommodates hydrophobic substrates
MDR Transporter (P-glycoprotein)
A single large protein with all 4 domains (2A + 2T)
Exports drugs and cytotoxic molecules from cells
Broad specificity, favouring small hydrophobic molecules
Mechanism: substrates diffuse into the bilayer and bind pockets in the T domains facing the hydrophobic core → ATP binds A domains → conformational change moves substrate to the extracellular surface
Contributes to chemotherapy resistance in cancer cells
CFTR and Airway Epithelium
CFTR is an ABC-family protein that functions as a regulated Cl⁻ channel (not as a pump)
Located in the apical membrane of airway epithelial cells
Activated by phosphorylation of the R (regulatory) domain + ATP hydrolysis by NBD1 and NBD2
Directly regulates Cl⁻ transport; indirectly regulates Na⁺ transport
Normal airways: proper Cl⁻ and Na⁺ transport → correct ion and water content in periciliary liquid (PCL) and airway surface liquid (ASL) → normal mucus viscosity → cilia move mucus effectively
Cystic Fibrosis (Clinical Application)
Caused by loss-of-function mutations in CFTR
Without functional CFTR: abnormal ion transport → PCL and ASL become dehydrated → mucus is too thick and viscous → cilia cannot move it
Consequences: bacteria trapped in mucus are not cleared → chronic infection → inflammation → tissue damage
Affected organs: lungs, pancreas, liver, GI system, urogenital system
Na⁺/K⁺ ATPase stoichiometry: 3 Na⁺ out, 2 K⁺ in, 1 ATP per cycle
SERCA stoichiometry: 2 Ca²⁺ pumped per ATP
Resting membrane potential: ~−70 mV (K⁺ equilibrium ~−59 mV + electrogenic pump contribution)
SGLT stoichiometry: 2 Na⁺ per 1 glucose
SGLT2 reabsorbs ~90% of glucose in the kidney
SGLT2 inhibitors (e.g. dapagliflozin, empagliflozin) are now widely prescribed for type 2 diabetes. They lower blood glucose by blocking glucose reabsorption in the kidney, causing excess glucose to be excreted in urine.
The MDR transporter explains why some cancers become resistant to chemotherapy. The pump exports the drug before it can act, and overexpression of MDR is a major clinical challenge in oncology.
Cystic fibrosis is the most common lethal autosomal recessive disease in people of European descent. Modern CFTR modulator therapies (e.g. elexacaftor/tezacaftor/ivacaftor) aim to restore partial Cl⁻ channel function.
Students often confuse channels and transporters. Channels form a continuous pore and do not undergo conformational changes during transport (fastest rate, passive only). Transporters cycle between conformations (slower, can be passive or coupled to an energy source).
Students sometimes think CFTR is a pump. It is classified in the ABC family but functions as a gated Cl⁻ channel, not as an active transporter.
Students often forget that the Na⁺/K⁺ ATPase is electrogenic. Because it exports 3 positive charges and imports only 2, it directly contributes a small component to the resting membrane potential.
Students sometimes assume secondary active transport uses ATP directly. It does not: it uses the energy stored in a pre-existing ion gradient (which was established by an ATP-driven pump).
⚠️ Know the difference between channels (fast, passive, gated) and transporters (conformational changes, slower).
⚠️ Understand the three types of channel gating: voltage-gated, ligand-gated, mechanically gated.
⚠️ Be able to distinguish uniport, symport, and antiport, and give an example of each.
⚠️ Know the stoichiometry of the Na⁺/K⁺ ATPase (3 Na⁺ out, 2 K⁺ in, 1 ATP) and SERCA (2 Ca²⁺ per ATP).
⚠️ Be able to explain the chloride shift in systemic and pulmonary capillaries.
⚠️ Understand how insulin regulates GLUT4 (fusion of recycling endosomes with plasma membrane → more transporters → higher Vₘₐₓ).
⚠️ Know the four types of ATP-powered pumps (P-type, F-type, V-type, ABC) and what distinguishes each.
⚠️ Be able to explain epithelial glucose transport: apical SGLT (symport, secondary active) + basal GLUT2 (uniport, passive) + basal Na⁺/K⁺ ATPase (primary active, maintains gradient).
⚠️ Understand the mechanism of action potentials: depolarisation via voltage-gated Na⁺ channels, repolarisation via channel inactivation and K⁺ leak, refractory period, unidirectional propagation.
⚠️ Know why cystic fibrosis causes thick mucus: loss of CFTR → impaired Cl⁻ transport → dehydrated airway surface → cilia cannot clear mucus → chronic infection.
True or False: Cholesterol increases membrane fluidity at all temperatures.
Fill in the blank: The Na⁺/K⁺ ATPase exports ______ Na⁺ ions and imports ______ K⁺ ions per ATP hydrolysed.
True or False: CFTR is an ATP-driven pump that actively transports Cl⁻ ions.
Fill in the blank: In secondary active transport, the energy source is a pre-existing ______ gradient, not ATP directly.
True or False: Action potential propagation is unidirectional because Na⁺ channels enter an inactivated state after firing.
Q: Why is flip-flop of phospholipids across the bilayer energetically unfavourable?
A: The polar headgroup of the phospholipid must pass through the hydrophobic core of the bilayer, which is thermodynamically costly. Specific flippase enzymes are required to catalyse this movement when needed.
Q: Explain how the Na⁺/K⁺ ATPase contributes to the resting membrane potential.
A: The pump exports 3 Na⁺ for every 2 K⁺ imported, producing a net export of one positive charge per cycle. This electrogenic activity adds a minor negative contribution to the resting potential. The major component comes from K⁺ leak channels, which allow K⁺ to flow out of the cell until its electrochemical gradient reaches equilibrium (~−59 mV).
Q: Describe the steps of the SERCA Ca²⁺ ATPase transport cycle.
A: (1) E1 conformation: high-affinity Ca²⁺ binding sites face the cytosol; Ca²⁺ and ATP bind. (2) ATP is hydrolysed and the α subunit is phosphorylated, favouring the E2 state. (3) E2 conformation: low-affinity sites now face the SR lumen; Ca²⁺ is released. (4) Empty sites favour dephosphorylation. (5) Dephosphorylation without Ca²⁺ returns the pump to the E1 conformation with high-affinity sites facing the cytosol again.
Q: How does insulin increase glucose uptake in skeletal muscle?
A: Insulin binds its receptor and activates a signalling pathway that stimulates the fusion of intracellular recycling endosomes (containing GLUT4 transporters) with the plasma membrane. This increases the number of GLUT4 transporters on the cell surface, raising the Vₘₐₓ of glucose uniport. The process is reversible: when insulin signalling decreases, GLUT4 is removed from the membrane by endocytosis.
Q: Distinguish between F-type and V-type pumps.
A: Both are structurally similar multi-subunit proton-handling complexes. F-type pumps (ATP synthase) operate in the direction of ATP synthesis in human mitochondria: H⁺ flows down its gradient through the F₀ sector, and the resulting rotation drives ATP production in the F₁ sector. V-type pumps (vacuolar ATPases) operate in the opposite direction: they hydrolyse ATP to pump H⁺ into lysosomes and endosomes, acidifying these compartments. Neither is phosphorylated during its cycle.
Q: Explain the chloride shift in systemic capillaries.
A: CO₂ diffuses from tissues into the RBC cytosol, where carbonic anhydrase converts it to HCO₃⁻ and H⁺. The anion exchanger AE1 (band 3) exports HCO₃⁻ out of the RBC into the plasma and imports Cl⁻ to balance the charge. This allows roughly 80% of CO₂ to be transported in the blood as dissolved HCO₃⁻.
Q: Why does cystic fibrosis lead to chronic lung infections?
A: Without functional CFTR, Cl⁻ transport out of airway epithelial cells is impaired, which also disrupts Na⁺ and water balance. The periciliary liquid (PCL) and airway surface liquid (ASL) become dehydrated, increasing mucus viscosity. Cilia cannot effectively move the thick mucus, so bacteria trapped in the mucus layer are not cleared. This leads to chronic infection, inflammation, and progressive tissue damage.
Membrane lipid chemistry (Lesson 7) builds on the fatty acid and amphiphilic molecule concepts from Lesson 2.
The protein structure principles from Lesson 3 (α helices, β barrels, domains) directly explain how integral membrane proteins span and interact with the bilayer.
ATP consumption by pumps (Lesson 9) closes the loop opened in Lesson 2: glycolysis, the Krebs cycle, and oxidative phosphorylation produce the ATP that the Na⁺/K⁺ ATPase, SERCA, and other pumps consume.
The ischemia cascade (Lesson 2) becomes more concrete once you understand exactly which ATP-dependent processes fail: ion pumping (Lessons 8–9), protein synthesis (Lesson 6), and osmotic regulation all depend on the ATP supply.
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