Cell Biology: Cell structure, organelles and membrane transport

🔬 Cell structure, organelles and membrane transport. Every disease is ultimately a disease of cells. The structure of the plasma membrane, the organelles and the cytoskeleton explains how drugs reach their targets, how ion channels set membrane potentials, how secretion and degradation work, and why defects in single components cause conditions from cystic fibrosis to lysosomal storage disease and primary ciliary dyskinesia.
Your four questions: Which compartment or organelle is involved? How does the molecule cross the membrane (diffusion, channel, carrier, pump, vesicle)? Which protein is defective, and what is its normal role? Which tissues depend most on it?

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Overview of the Eukaryotic Cell

• The adult body contains about 37 trillion cells of over 200 types, all with the same genome but different gene expression.
• Compartments: plasma membrane, cytoplasm (cytosol plus organelles), nucleus, and membrane-bound organelles (endoplasmic reticulum, Golgi apparatus, lysosomes, peroxisomes, mitochondria, endosomes).
• Cells without a nucleus or mitochondria - mature red blood cells (glycolysis only; cannot synthesise proteins); platelets have no nucleus but contain mitochondria.
• Prokaryotes (bacteria) differ: no nucleus, 70S ribosomes (target of many antibiotics), cell wall (peptidoglycan - target of β-lactams), no membrane-bound organelles - the basis of selective toxicity.

The Plasma Membrane

• Fluid mosaic model - a phospholipid bilayer with embedded and peripheral proteins, cholesterol (modulates fluidity) and glycolipids/glycoproteins (glycocalyx - cell recognition, blood group antigens).
• Membrane proteins: receptors, channels, carriers, pumps, enzymes, adhesion molecules, cell identity markers (MHC/HLA).
• Lipid rafts - cholesterol-rich microdomains organising signalling proteins.
• Phosphatidylserine - normally on the inner leaflet; exposed on the outer leaflet in apoptosis (an "eat me" signal) and in activated platelets (procoagulant surface).
• Permeability: small non-polar molecules (O₂, CO₂, steroid hormones, lipid-soluble drugs, anaesthetics) cross freely; ions and polar molecules need proteins.
• Drug implications: lipid-soluble drugs cross the blood–brain barrier and placenta; ionised drugs are trapped (ion trapping - alkalinising urine increases salicylate excretion).

Membrane Transport Mechanisms

Mechanism	Energy	Example
Simple diffusion	None (down gradient)	O₂, CO₂, lipid-soluble drugs
Facilitated diffusion (carrier)	None	GLUT transporters (GLUT1 - red cells, brain; GLUT2 - liver, β cells, gut basolateral; GLUT4 - muscle and fat, insulin-dependent)
Channels	None	Na⁺, K⁺, Ca²⁺, Cl⁻ channels; aquaporins (water)
Primary active transport	ATP	Na⁺/K⁺-ATPase (digoxin inhibits), H⁺/K⁺-ATPase (PPIs inhibit), Ca²⁺-ATPase (SERCA), ABC transporters (P-glycoprotein - drug efflux, CFTR)
Secondary active transport (co-transport)	Na⁺ gradient	SGLT1 (gut glucose - basis of oral rehydration solution), SGLT2 (renal glucose - gliflozins), NKCC2 (loop diuretics), NCC (thiazides), Na⁺/Ca²⁺ exchanger, Na⁺/H⁺ exchanger
Vesicular transport	ATP	Endocytosis, exocytosis

• Osmosis - water moves towards higher solute concentration through aquaporins; cells swell in hypotonic and shrink in hypertonic fluids (hence the dangers of rapid sodium changes for brain cells).
• P-glycoprotein - efflux pump in gut, blood–brain barrier and kidney; inhibitors (clarithromycin, verapamil, amiodarone, ciclosporin) raise levels of substrates such as digoxin and DOACs; also contributes to cancer multidrug resistance.

Ion Channels and Channelopathies

• Voltage-gated channels (Na⁺, K⁺, Ca²⁺) generate and shape action potentials; ligand-gated channels (nicotinic acetylcholine, GABA-A, NMDA/AMPA glutamate, 5-HT₃) mediate fast synaptic transmission.
• Drugs acting on channels: local anaesthetics and class I antiarrhythmics (Na⁺ channel blockers), carbamazepine, phenytoin and lamotrigine (Na⁺), calcium channel blockers (L-type), sulfonylureas (K-ATP channel closure), amiodarone (K⁺), benzodiazepines (GABA-A), ondansetron (5-HT₃), ketamine (NMDA).

Channelopathy	Channel	Features
Cystic fibrosis	CFTR (Cl⁻)	Thick secretions - lung, pancreas, sweat (high sweat chloride), male infertility
Long QT syndrome	K⁺ (KCNQ1, KCNH2) or Na⁺ (SCN5A)	Syncope, torsades de pointes, sudden death (triggers - exercise/swimming, sudden noise, sleep)
Brugada syndrome	Na⁺ (SCN5A)	Coved ST elevation V1–V3; VF and sudden death (often at rest/sleep, fever unmasks)
Myasthenia gravis (autoimmune)	Nicotinic ACh receptor antibodies	Fatigable weakness
Lambert–Eaton syndrome (autoimmune)	Presynaptic voltage-gated Ca²⁺ channel antibodies	Proximal weakness improving with exercise, autonomic features; small cell lung cancer
Periodic paralyses	Ca²⁺ or Na⁺ channels	Episodes of weakness with low or high K⁺ (thyrotoxic periodic paralysis)
Malignant hyperthermia	Ryanodine receptor (RYR1)	Hyperthermia and rigidity with volatile anaesthetics/suxamethonium
Dravet syndrome	Na⁺ (SCN1A)	Severe childhood epilepsy - avoid sodium-channel blockers

Endocytosis, Exocytosis and Protein Trafficking

• Endocytosis: phagocytosis (large particles - neutrophils, macrophages), pinocytosis (fluid), receptor-mediated endocytosis via clathrin-coated pits (LDL receptor - defective in familial hypercholesterolaemia; transferrin receptor).
• Exocytosis: constitutive (continuous - collagen, plasma proteins) or regulated (Ca²⁺-triggered - neurotransmitters, insulin, mast cell granules). SNARE proteins mediate vesicle fusion - cleaved by botulinum toxin (blocks acetylcholine release → flaccid paralysis) and tetanus toxin (blocks inhibitory neurotransmitter release in the cord → spastic paralysis).
• Protein trafficking: proteins for secretion or membranes are made on the rough ER, modified in the Golgi, and sorted by signal sequences; mannose-6-phosphate targets enzymes to lysosomes (defective in I-cell disease).

Nucleus, Ribosomes and Endoplasmic Reticulum

• Nucleus - double membrane (nuclear envelope) with pores; contains chromatin (DNA + histones) and the nucleolus (ribosomal RNA synthesis). Lamins support the envelope (laminopathies - progeria, some muscular dystrophies).
• Ribosomes - 80S in eukaryotes (60S + 40S); 70S in bacteria (50S + 30S - targets of macrolides, aminoglycosides, tetracyclines, linezolid, chloramphenicol). Free ribosomes make cytosolic proteins; ribosomes on the rough ER make secreted and membrane proteins.
• Rough ER - protein synthesis, folding and quality control; misfolded proteins trigger the unfolded protein response (ER stress) and ER-associated degradation (via proteasome). Prominent in plasma cells and pancreatic acinar cells.
• Smooth ER - lipid and steroid synthesis (adrenal cortex, gonads), drug metabolism (cytochrome P450) in hepatocytes - proliferates with enzyme-inducing drugs; calcium storage (sarcoplasmic reticulum in muscle).
• Proteasome - degrades ubiquitin-tagged proteins (target of bortezomib in myeloma).

Golgi, Lysosomes and Peroxisomes

• Golgi apparatus - modifies (glycosylation), sorts and packages proteins for secretion, membranes or lysosomes.
• Lysosomes - acidic (pH about 4.5) organelles containing hydrolytic enzymes; degrade material from endocytosis, phagocytosis and autophagy (recycling of damaged organelles). Defects → lysosomal storage disorders (Gaucher, Tay–Sachs, Fabry, Pompe, mucopolysaccharidoses).
• Hydroxychloroquine and chloroquine raise lysosomal pH (part of their immunomodulatory action).
• Peroxisomes - oxidise very-long-chain fatty acids, make plasmalogens (myelin) and break down hydrogen peroxide (catalase); disorders include adrenoleukodystrophy and Zellweger syndrome.

Mitochondria

• Double membrane; the inner membrane folds into cristae containing the electron transport chain and ATP synthase.
• Functions: ATP production (oxidative phosphorylation), β-oxidation, TCA cycle, ketogenesis, part of the urea cycle and haem synthesis, calcium buffering, heat production (brown fat), and apoptosis (cytochrome c release - intrinsic pathway).
• Own DNA (mtDNA) - circular, 37 genes, maternally inherited; many copies per cell → heteroplasmy.
• Drug toxicity: nucleoside reverse transcriptase inhibitors (older agents - lactic acidosis, neuropathy), linezolid (lactic acidosis, neuropathy with prolonged use), aminoglycoside ototoxicity in susceptible mtDNA variants, valproate (POLG disease), metformin (complex I).

Cytoskeleton, Cilia and Cell Junctions

• Microfilaments (actin) - cell shape, movement, muscle contraction (with myosin), cytokinesis.
• Intermediate filaments - mechanical strength; tissue-specific, used as immunohistochemistry markers in tumour diagnosis: cytokeratins (epithelial - carcinomas), vimentin (mesenchymal - sarcomas), desmin (muscle), GFAP (glial cells - gliomas), neurofilaments (neurons).
• Microtubules (tubulin) - intracellular transport, mitotic spindle, cilia and flagella. Drugs: vincristine and vinblastine (inhibit polymerisation - neuropathy), taxanes (paclitaxel - stabilise microtubules), colchicine (inhibits polymerisation in neutrophils - gout), griseofulvin, mebendazole (parasite tubulin).
• Cilia - motile cilia (airways, fallopian tubes, ependyma; 9+2 microtubule arrangement with dynein arms) and primary (sensory) cilia. Primary ciliary dyskinesia (dynein defects) - chronic sinusitis, bronchiectasis, otitis media, infertility, situs inversus in about half (Kartagener's syndrome). Ciliopathies of primary cilia include polycystic kidney disease.
• Cell junctions: tight junctions (seal - blood–brain barrier, gut epithelium), adherens junctions (cadherins - loss of E-cadherin in diffuse gastric cancer and lobular breast cancer), desmosomes (anchoring - antibodies to desmoglein in pemphigus vulgaris → intraepidermal blisters), hemidesmosomes (anchor to basement membrane - antibodies in bullous pemphigoid → subepidermal blisters), gap junctions (connexins - electrical coupling in heart and smooth muscle).
• Basement membrane - type IV collagen, laminin; antibodies to type IV collagen in anti-GBM (Goodpasture's) disease; Alport syndrome (type IV collagen gene defect - nephritis and deafness).

Cell Structure at a Glance

Component	Clinical link
Na⁺/K⁺-ATPase	Digoxin target
SGLT1 / SGLT2	Oral rehydration solution / gliflozins
CFTR	Cystic fibrosis
SNAREs	Botulinum and tetanus toxins
70S ribosome	Antibiotic target
Smooth ER	CYP450 drug metabolism, steroid synthesis
Lysosome	Storage disorders
Microtubules	Vincristine, taxanes, colchicine
Dynein	Primary ciliary dyskinesia
Desmosomes / hemidesmosomes	Pemphigus / pemphigoid

Spot the Diagnosis

• Recurrent chest infections, sinusitis, infertility and dextrocardia. → Kartagener's syndrome (primary ciliary dyskinesia).
• Flaccid blisters and oral erosions with Nikolsky's sign. → Pemphigus vulgaris (anti-desmoglein - desmosomes).
• Tense blisters on the limbs of an 80-year-old. → Bullous pemphigoid (hemidesmosomes).
• Descending flaccid paralysis with fixed dilated pupils after injecting heroin. → Wound botulism (SNARE cleavage).
• Syncope while swimming in a teenager with QTc 520 ms. → Long QT syndrome type 1 (KCNQ1).

Exam-style Scenarios

• Scenario. A patient on digoxin is started on clarithromycin and develops nausea and xanthopsia. Why?
  Answer: Clarithromycin inhibits P-glycoprotein (and CYP3A4), reducing digoxin excretion → toxicity. Check digoxin level and potassium; withhold digoxin; consider an alternative antibiotic.
• Scenario. Why does oral rehydration solution contain glucose as well as sodium?
  Answer: SGLT1 in the small intestine co-transports sodium and glucose; water follows by osmosis. This pathway works even in secretory diarrhoea (e.g. cholera), when other sodium absorption is impaired.
• Scenario. A tumour stains positive for cytokeratin and negative for vimentin and CD45. What type of tumour is it?
  Answer: A carcinoma (epithelial origin) - cytokeratin is an epithelial intermediate filament; CD45 negativity excludes lymphoma.

Key Points

• Selective toxicity of antibiotics exploits differences between bacterial and human cells (cell wall, 70S ribosomes).
• Know the transporters behind common drugs (Na⁺/K⁺-ATPase, SGLT2, NKCC2, NCC, H⁺/K⁺-ATPase).
• Channelopathies cause arrhythmias, epilepsy, paralysis and cystic fibrosis.
• Intermediate filaments are diagnostic tumour markers.
• Desmosomes - pemphigus; hemidesmosomes - pemphigoid.

Further Reading

• Alberts B et al. Molecular Biology of the Cell
• Lodish H et al. Molecular Cell Biology
• Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology (cell biology chapters)