Cell Biology: Lysosomes, Cell Membrane & Transport, Cytoskeleton

1. LYSOSOMES

Structure

• The lysosomal pH is ~4.8-5.0, maintained by proton pumps in the lysosomal membrane that actively pump H⁺ into the lumen.
• At the neutral cytosolic pH (~7.2), leaked lysosomal enzymes become inactive - a key safety mechanism protecting the cell.
• Lysosomes are most numerous in cells with high phagocytic activity (macrophages, neutrophils).

Lysosomal Enzyme Targeting (M6P Pathway)

Clinical pearl - I-cell disease: Phosphotransferase deficiency means M6P tags cannot be added, so lysosomal enzymes are secreted extracellularly instead of reaching lysosomes. Cells accumulate undigested material (inclusions), affecting the skeleton and nervous system.

Functions of Lysosomes

• Residual bodies accumulate as lipofuscin granules in long-lived post-mitotic cells (neurons, cardiac muscle).

Lysosomal Storage Diseases

2. CELL MEMBRANE AND TRANSPORT (★ HIGH YIELD)

Cell Membrane Structure

• Channel proteins - have watery pores allowing nearly free movement of water and selected ions (e.g., aquaporins, ion channels)
• Carrier proteins - bind specific molecules/ions, undergo conformational change to transport them across

A. DIFFUSION (Passive Transport - no energy required)

Simple Diffusion

• Random molecular movement down a concentration gradient through lipid bilayer interspaces or protein channels.
• Rate follows Fick's Law: proportional to the concentration gradient, membrane surface area, and membrane permeability.
• Factors driving diffusion across a membrane:
  1. Concentration gradient (high → low)
  2. Electrical potential (for ions): positive charge attracts anions, repels cations
  3. Pressure difference: higher pressure side has more kinetic energy → net movement toward lower pressure

Nernst Potential

Facilitated Diffusion

• Uses carrier proteins - moves substances down their concentration gradient but faster than simple diffusion.
• No energy required - movement is still from high to low concentration.
• Example: glucose transport into cells (GLUT transporters); the rate shows saturation kinetics.

Osmosis

• Net diffusion of water through a selectively permeable membrane from lower solute concentration → higher solute concentration.
• The osmotic pressure that would exactly prevent net water movement is the osmotic pressure of the solution.
• Red blood cell membrane allows water diffusion equivalent to ~100× its volume per second.

B. ACTIVE TRANSPORT (Energy required, moves against gradient)

Primary Active Transport

• Uses ATP directly. Key example: Na⁺-K⁺ ATPase pump

1. 3 Na⁺ bind on the inside of the pump
2. 2 K⁺ bind on the outside
3. ATPase activity is activated → ATP is cleaved to ADP + Pᵢ
4. Conformational change extrudes 3 Na⁺ out and brings 2 K⁺ in
5. Net result: one positive charge moved outward per cycle (electrogenic)

• Maintains low intracellular Na⁺ and high intracellular K⁺
• Controls cell volume - without it, osmotic entry of water would cause cells to swell and burst (intracellular anions attract cations → osmosis)
• Generates the resting membrane potential (electrogenic - produces inside-negative)
• In electrically active neurons: 60-70% of total energy expenditure goes to this pump

The Na⁺-K⁺ pump can run in reverse - if electrochemical gradients are experimentally large enough, it synthesizes ATP from ADP + Pi.

Secondary Active Transport (Co-transport / Counter-transport)

• Uses the Na⁺ gradient created by Na⁺-K⁺ ATPase as the energy source (indirect).
• Co-transport (symport): Na⁺ and another solute move in the same direction (e.g., Na⁺-glucose co-transporter in intestinal epithelium)
• Counter-transport (antiport): Na⁺ and another solute move in opposite directions (e.g., Na⁺-Ca²⁺ exchanger - Ca²⁺ pumped out while Na⁺ enters)

Summary Table: Types of Transport

C. Vesicular Transport (Bulk Transport)

• Endocytosis: cell membrane invaginates to engulf extracellular material
  • Phagocytosis: large particles (bacteria, cell debris) - mainly in macrophages/neutrophils
  • Pinocytosis: fluid droplets with dissolved substances
  • Receptor-mediated endocytosis: specific molecules bind cell surface receptors → clathrin-coated pit → vesicle (e.g., LDL receptor pathway)
• Exocytosis: vesicle fuses with plasma membrane to release contents extracellularly (opposite of endocytosis)

3. CYTOSKELETON

A. Microtubules

• Diameter: 25 nm (hollow tubes); walls ~5 nm thick, inner cavity 15 nm
• Composition: α- and β-tubulin heterodimers polymerize into 13-protofilament hollow tubes
  • γ-tubulin: associated with centrosomes (MTOCs) and initiates microtubule nucleation
• Polarity: "+" end (plus end) elongates rapidly; "-" end (minus end) typically embedded in the MTOC/centrosome near the nucleus
• Dynamics: temperature-sensitive; assembly at (+) end, disassembly at (-) end; GTP binding facilitates formation
• Functions:
  • Tracks for molecular motor proteins (kinesins, dyneins) to transport vesicles, organelles, secretory granules, mitochondria
  • Form the mitotic spindle - segregates sister chromatids during cell division
  • Core of primary cilia (9+0 arrangement) - regulate proliferation/differentiation; defects cause polycystic kidney disease
  • Core of motile cilia (9+2 arrangement) and flagella

• Colchicine / Vinca alkaloids (vincristine, vinblastine): inhibit microtubule polymerization → disrupt mitotic spindle → arrest cell division
• Taxol (paclitaxel): stabilizes microtubules (prevents depolymerization) → also arrests mitosis

B. Intermediate Filaments

• Diameter: 8-14 nm (between micro and macro - hence "intermediate")
• Composition: large, heterogeneous family of ropelike polymers
• Key property: do not actively reorganize like actin/microtubules; provide tensile strength and resist mechanical stress
• Tissue-specific expression (used as tumor markers):

• Connect desmosomes and hemidesmosomes → link neighboring cells and ECM mechanically
• Absent/abnormal IF → skin blistering (epidermolysis bullosa)

C. Microfilaments (Actin Filaments)

• Diameter: 5-9 nm (thinnest)
• Composition: G-actin (globular monomers) polymerize into F-actin (filamentous, double-stranded helix)
• Most abundant protein in mammalian cells - up to 15% of total cellular protein; sequence highly conserved (88% identical between yeast and rabbit)
• Polarity: new subunits added at "+" end, removed from "-" end (actin treadmilling)
• Functions:
  • Cell shape changes and migration (lamellipodia formation, focal adhesion complexes)
  • Reach tips of microvilli (intestinal brush border)
  • Interaction with myosin → muscle contraction (sarcomeres) and non-muscle motility
  • Vesicular transport and epithelial barrier regulation
  • Actin nucleating proteins (e.g., Arp2/3 complex) regulate branching/polymerization

Molecular Motors

Clinical Correlations - Cytoskeleton

• Polycystic kidney disease: mutations in proteins of the primary cilia complex (microtubule-based)
• Kartagener syndrome (primary ciliary dyskinesia): dynein arm defects → immotile cilia → bronchiectasis, situs inversus, male infertility
• E-cadherin loss (linked to actin via adherens junctions): explains discohesive invasion in lobular breast carcinoma and some gastric cancers
• Epidermolysis bullosa: defective keratin or desmosomal proteins → skin blistering under mechanical stress

• Guyton and Hall Textbook of Medical Physiology - Chapters 2 & 4
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Chapter 1
• Ganong's Review of Medical Physiology - Chapter 2
• Junqueira's Basic Histology - Text and Atlas, 17e - Chapter 2

📋 What's Covered - Navigation Index

🫁 GIT (7 Topics)

1. Salivary Glands - 3 major pairs, saliva composition, neural control flowchart
2. GIT Secretions - All regions + gastric cell types table
3. Enteric Nervous System - Auerbach's vs Meissner's plexus, peristaltic reflex flowchart
4. Hormonal & Neural Control of Gastric Secretion - 3 phases flowchart, parietal cell HCl mechanism, GIT hormones table
5. Liver - All 5 categories of function, bilirubin metabolism flowchart
6. Pancreas - Exocrine enzymes, control of secretion (Secretin + CCK synergy)
7. Biliary Secretions & Gallbladder - Enterohepatic circulation flowchart, gallbladder functions

❤️ Cardiac (5 Topics)

1. Cardiac Cycle - All 7 phases (A-G) with valves, heart sounds, ECG correlation
2. ECG - All waves/intervals and their electrical events
3. Cardiac Output - Formulas + determinants diagram
4. Conduction System - SA→AV→Bundle→Purkinje pathway with velocities
5. Definitions - Systole, Diastole, Preload, Afterload, SV, EF

🧠 ANS (4 Topics)

1. Divisions of ANS - Sympathetic vs Parasympathetic overview
2. Comparison Table - 10 features compared side-by-side
3. Organ Effects - Complete table (heart, lungs, GI, eyes, bladder, glands)
4. ACh & NE Synthesis - Step-by-step biosynthetic pathways with enzymes

🧬 Neural/CNS (9 Topics)

1. Neuron Classification - By processes (uni/bi/multipolar), function, fiber type (Aα-C)
2. Action Potential - Phases, ion movements, voltage-gated channels
3. Refractory Period - ARP vs RRP, clinical significance (cardiac tetany prevention)
4. NT vs Neuromodulators - 7-feature comparison table
5. Cerebrum - Overview + functional map
6. Lobes of Brain - 6 lobes with key areas and functions
7. Cerebellum - 3 divisions, cortical layers (Purkinje cells!), deep nuclei, lesion signs
8. Brainstem - Midbrain/Pons/Medulla contents, CN nuclei, vital centers
9. Synapse Types - Structural types, transmission sequence flowchart, EPSP/IPSP
10. Types of Sleep - NREM stages + REM, sleep architecture, neurotransmitters of sleep