General Principles and Energy Production in Medical Physiology
Based on Ganong’s Review of Medical Physiology (26th ed.), Chapter 1.
Core idea: life requires continuous energy transfer; ATP is the primary energy currency in the body.
Energy production pathways provide energy for muscle contraction, active transport, and biosynthetic reactions; energy losses and inefficiencies exist.
ATP hydrolysis and energy release:
ATP → ADP releases usable energy for cellular work (muscle contraction, active transport, synthesis).
Further hydrolysis of ADP → AMP releases additional energy (lower-energy phosphate bond sequences sustain ongoing work).
Oxidation and reduction (redox):
Oxidation: loss of hydrogen or electrons; addition of oxygen or loss of hydrogen; gains or losses of electrons drive energy capture.
Reduction: gain of electrons or hydrogen; often coupled to oxidation steps elsewhere.
Catalysis of biological oxidations:
Enzymes accelerate oxidation/reduction reactions.
Cofactors (ions) or coenzymes (organic molecules, e.g., NAD⁺, NADP⁺) act as carriers to shuttle electrons or groups.
Coenzymes can catalyze multiple reactions; they are not consumed in the overall reaction.
Oxidative phosphorylation (mitochondrial ATP production):
Protons pumped across the mitochondrial membrane create a proton gradient.
The gradient drives ATP synthase to form ATP from ADP + Pi.
About 90% of basal O₂ consumption occurs in mitochondria; ~80% of that O₂ consumption is coupled to ATP synthesis.
ATP utilization in the resting cell (percent of total cellular ATP consumption):
Protein synthesis: ~27%
Na⁺/K⁺ ATPase (membrane potential maintenance): ~24%
Gluconeogenesis: ~9%
Ca²⁺ ATPase (cytosolic Ca²⁺ homeostasis): ~6%
Myosin ATPase (muscle contraction): ~5%
Ureagenesis: ~3%
Energy carriers and cellular compartments:
ATP is produced primarily in mitochondria via oxidative phosphorylation; glycolysis in the cytosol provides some ATP and reducing equivalents.
Most ATP generated from carbon fuels is ultimately derived from oxidation of substrates in mitochondria.
Mitochondria: structure and genetics
Mitochondria are numerous per cell; inner membrane contains cristae where oxidative phosphorylation occurs; matrix houses enzymes of the citric acid cycle.
Mitochondrial genome: double-stranded circular DNA (~16,500 bp).
~99% of mitochondrial proteins are encoded by nuclear DNA and imported.
Mitochondria are inherited maternally; high mutation rate relative to nuclear DNA; mutations linked to mitochondrial diseases, especially in high-energy-demand tissues.
Summary: energy production is a integrated process involving substrate oxidation, electron transport, proton motive force, and ATP synthesis; tight coupling to cellular energy demands and biosynthetic needs.
Body Fluid Compartments and Distribution
Body composition (average young adult male): ~18% protein, ~7% minerals, ~15% fat, ~60% water.
Body water is distributed between two main compartments:
Intracellular fluid (ICF): inside cells; ~2/3 of total body water (~40% of body weight).
Extracellular fluid (ECF): outside cells; ~1/3 of total body water (~20% of body weight); includes plasma and interstitial fluid.
Extracellular Fluid (ECF) components:
Plasma (blood) fluid ~5% body weight.
Interstitial fluid ~15% body weight.
Interstitial fluid and fluid movement:
Cells reside in an interstitial fluid environment; nutrients and oxygen diffuse from capillaries into interstitial fluid and then into cells; wastes move back into interstitial fluid and blood.
Fluid movement is tightly regulated; edema = abnormal buildup of interstitial fluid.
Diagrammatic breakdown (relative proportions):
Plasma: 5% body weight
Extracellular fluid: 20% body weight
Interstitial fluid: 15% body weight (of body weight, within ECF)
Intracellular fluid: 40% body weight
pH, Buffers, and Acid-Base Physiology
pH definition:
pH = −log₁₀[H⁺]
Pure water at 25 °C has pH 7.0; [H⁺] = 10⁻⁷ M.
Each unit change in pH represents a 10× change in [H⁺].
Physiologic pH ranges:
Normal plasma: pH 7.35–7.45 (slightly alkaline).
Gastric fluid: ~pH 3.0 (acidic).
Pancreatic secretions: ~pH 8.0 (alkaline).
Importance of pH:
pH affects enzyme activity and protein structure; small pH changes can significantly affect biochemical equilibria.
Acids, bases, and buffers:
Acids donate H⁺; bases accept H⁺.
Strong acids/bases fully dissociate; most physiologic acids/bases are weak and partially dissociate.
Buffers bind or release H⁺ to maintain pH when acids/bases are added.
Isohydric principle: in a mixed buffer solution, all buffers share the same [H⁺]; measuring one buffer reveals others.
Henderson–Hasselbalch equation:
ext{pH} = ext{p}K_a + \log\left(\frac{[A^-]}{[HA]}\right)
Buffering is most effective when pH ≈ pKₐ; when [A⁻]/[HA] is balanced, buffering capacity is maximal.
Carbonic acid–bicarbonate buffer system:
CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻
This buffer resists pH changes and is tightly linked to respiratory CO₂ removal.
Lungs regulate CO₂, aiding pH homeostasis.
Other buffers:
Phosphate buffer system
Protein buffers (hemoglobin, plasma proteins, etc.)
Practical implications:
Acid-base disturbances are managed by buffering, respiratory regulation, and renal excretion of acids/bases.
Diffusion, Osmosis, and Osmolality/Osmolarity
Diffusion:
Random movement of particles from high to low concentration; net flux follows a concentration gradient.
Time to equilibrium scales with distance squared, t ∝ (distance)².
Factors affecting diffusion rate (Fick’s Law): surface area, concentration gradient, and membrane thickness (boundary thickness).
Osmosis:
Movement of water across a selectively permeable membrane from low solute concentration to high solute concentration.
Membrane must be permeable to water but impermeable to solute.
Osmotic pressure:
Pressure required to stop water movement into the more concentrated solution; a colligative property depending on solute particle number, not identity.
Osmoles and osmolality/osmolarity:
Osmole (Osm) = gram molecular weight ÷ number of freely moving particles per molecule in solution.
Milliosmoles (mOsm) common in physiology.
Osmolarity: Osmoles per liter of solution; osmolality: Osmoles per kilogram of solvent (temperature dependent for osmolarity).
In body fluids, osmolality approximates osmoles per liter of water due to nearly unit density.
Osmolality and tonicity (concentration relative to plasma):
Isotonic: same osmolality as plasma; no net water movement.
Hypertonic: higher osmolality; water moves out of cells causing shrinkage.
Hypotonic: lower osmolality; water moves into cells causing swelling.
Plasma osmolality contributors (approximate):
Na⁺ and accompanying anions ~270 mOsm/L
Other cations/anions: small contributions
Plasma proteins: < 2 mOsm/L (high molecular weight)
Glucose and urea: ~5 mOsm/L each (can rise in hyperglycemia or uremia)
Donnan Effect and Ionic Distributions
Donnan effect: presence of non-diffusible ions (e.g., proteins) on one side of a semipermeable membrane affects distribution of permeable ions, altering osmotic balance and ionic composition.
Physiologic consequences:
Cell volume regulation: Proteins inside cells increase osmotically active particles; Na⁺/K⁺ ATPase pump maintains volume and pressure.
Membrane potential: Unequal ion distribution generates a membrane potential; proteins contribute to this asymmetry.
Capillary exchange influenced by Donnan forces due to plasma proteins vs interstitial proteins.
Gibbs–Donnan equation (equilibrium concept): at equilibrium, the sum of charges on each side balances; applied to cation–anion pairs of the same valence.
Membrane Potentials and Ion Transport
Forces acting on ions across membranes:
Chemical (concentration) gradients and electrical gradients together determine ion movement.
Equilibrium potential (E_ion) occurs when forces balance; calculated via the Nernst equation.
Chloride (Cl⁻) example:
Higher [Cl⁻] outside (ECF) drives Cl⁻ inward by chemical gradient; interior is negative, electrical gradient pushes Cl⁻ outward.
At equilibrium, E_Cl ≈ −70 mV (resting potential axis explained by gradients).
Potassium (K⁺) example:
Higher [K⁺] inside drives K⁺ outward by chemical gradient; negative interior pulls K⁺ inward.
EK ≈ −90 mV; resting potential around −70 mV; indicates additional factors limit diffusion beyond gradient alone.
Sodium (Na⁺) example:
Higher outside [Na⁺] drives Na⁺ inward by chemical gradient; negative interior also favors inward movement.
ENa ≈ +60 mV; would cause Na⁺ influx if unregulated.
Na⁺/K⁺ ATPase (sodium–potassium pump):
Actively pumps 3 Na⁺ out and 2 K⁺ in per ATP hydrolysis; maintains low intracellular Na⁺ and high intracellular K⁺.
This pump is electrogenic and contributes directly to the resting membrane potential.
Establishment of membrane potential:
K⁺ efflux via K⁺ channels tends to hyperpolarize the membrane, but the inward electrical gradient pulls K⁺ back in; a steady state maintains a negative resting potential.
Only a tiny fraction of total ions participate in maintaining the membrane potential; overall charge neutrality is preserved across the membrane surface.
Energy Production: ATP and Cellular Energetics (continued)
ATP as the primary high-energy phosphate currency:
ATP hydrolysis provides energy for contraction, transport, and biosynthesis.
ATP → ADP is the main energetic step; ADP → AMP provides additional energy release (less common but occurs in some pathways).
Oxidative phosphorylation overview:
Proton gradient across inner mitochondrial membrane drives ATP synthesis.
Majority of cellular O₂ consumption occurs in mitochondria and links to ATP production.
Distribution of cellular ATP use (reiterated):
Synthesis, membrane potential maintenance, gluconeogenesis, Ca²⁺ handling, muscle contraction, ureagenesis.
Subcellular Energy: Mitochondria, DNA, and Bioenergetics
Mitochondria:
Numerous per cell; outer membrane and highly folded inner membrane (cristae).
Oxidative phosphorylation complexes reside on cristae; mitochondrial matrix houses enzymes of the TCA cycle.
Own genome: circular DNA (~16,500 bp); most mitochondrial proteins encoded by nuclear DNA and imported.
Maternal inheritance; high mutation rate; mutations linked to energy-demanding tissue diseases.
Cellular organelles overview (context for energy and metabolism):
Nucleus (DNA storage, transcription)
Endoplasmic reticulum (RER with ribosomes for protein synthesis; SER for lipid synthesis and detoxification)
Golgi apparatus (protein/lipid modification and packaging)
Lysosomes (acid hydrolases for digestion)
Peroxisomes (beta-oxidation of very-long-chain fatty acids; detoxification)
Mitochondria (ATP production)
Cytoskeleton (microtubules, intermediate filaments, microfilaments) for cell shape and transport
Nucleotides, Nucleic Acids, and DNA/RNA Biology
Nucleosides vs nucleotides:
Nucleoside = sugar + nitrogenous base (purine or pyrimidine).
Nucleotide = nucleoside + inorganic phosphate (phosphoric acid residue).
Functions of nucleotides:
Backbone components of RNA and DNA; coenzymes (e.g., NAD⁺, NADP⁺, ATP); regulatory molecules.
Nucleobases and nucleosides:
Purines: Adenine (A), Guanine (G)
Pyrimidines: Cytosine (C), Uracil (U; RNA only), Thymine (T; DNA only)
DNA structure:
Two antiparallel nucleotide chains; A pairs with T; G pairs with C via hydrogen bonds.
Double helix stabilized by hydrogen bonding and base stacking; compacted with histones into chromosomes.
Human genome: diploid number 46 chromosomes.
DNA replication and gene expression:
DNA replication is semi-conservative; DNA polymerase synthesizes new strands; sister chromatids separate in mitosis.
Mitosis yields identical genetic material in daughter cells; meiosis halves chromosome number for gametes.
Gene expression is regulated spatially (cell type) and temporally (developmental stage); not all genes are transcribed in every cell.
RNA and protein synthesis:
RNA synthesized in nucleus from DNA template (transcription) by RNA polymerase.
RNA types: mRNA (coding), tRNA (amino acid delivery), rRNA (ribosome structural/enzymatic roles); microRNAs and others exist.
Translation occurs on ribosomes; codons on mRNA specify amino acids; tRNA matches codons with anticodons; ribosome catalyzes peptide bond formation.
Central dogma and cell cycle basics (link to gene expression):
DNA -> RNA -> protein; replication for cell division; cell cycle phases govern when DNA is replicated and when cells divide.
Amino Acids, Proteins, and Metabolism
Amino acids as building blocks of proteins:
20 standard amino acids; denoted by 3-letter or 1-letter codes (e.g., Ala, A for alanine).
Classified by side chains: aliphatic, hydroxyl-substituted, sulfur-containing, aromatic, acidic, basic, etc.
Essential amino acids must be obtained from the diet; conditionally essential amino acids (e.g., arginine, histidine during growth/recovery); nonessential can be synthesized.
Peptides vs proteins:
Peptides: 2–100 amino acids; proteins: ≥100 amino acids.
Amino acids in proteins (typical table categories):
Aliphatic: Alanine (Ala, A); Valine (Val, V); Leucine (Leu, L); Isoleucine (Ile, I).
Hydroxyl-substituted: Serine (Ser, S); Threonine (Thr, T).
Sulfur-containing: Cysteine (Cys, C); Methionine (Met, M); Selenocysteine.
Aromatic: Phenylalanine (Phe, F); Tyrosine (Tyr, Y); Tryptophan (Trp, W).
Acidic/amide: Aspartic acid (Asp, D); Asparagine (Asn, N); Glutamine (Gln, Q); Glutamic acid (Glu, E); gamma-carboxyglutamic acid (Gla).
Basic: Arginine (Arg, R); Lysine (Lys, K); Histidine (His, H); Proline (Pro, P); Hydroxyproline (Hyp).
Amino acid metabolism and transamination:
Transaminases transfer amino groups; amino acids feed carbon skeletons into energy metabolism or gluconeogenesis.
Catabolism classifications (entry points into energy pathways):
Ketogenic amino acids: leucine, isoleucine, phenylalanine, tyrosine → converted to acetoacetate (a ketone body) for energy or ketone body synthesis.
Glucogenic (gluconeogenic) amino acids: alanine and many others → converted into intermediates that can become glucose.
Carbohydrates, Glucose Metabolism, and Lipids
Carbohydrates basics:
Monosaccharides (pentoses and hexoses): e.g., ribose (structural roles in nucleotides) and glucose (energy and signaling roles).
Disaccharides and polysaccharides (e.g., sucrose, glycogen).
Glycoproteins: sugars attached to proteins aid in targeting and signaling.
Dietary sugars and glucose:
Most dietary carbohydrates are hexose polymers; main circulating sugar is glucose.
Normal fasting plasma glucose: 70–110 mg/dL (venous); arterial glucose is 15–30 mg/dL higher.
Glucose metabolism:
Glucose phosphorylation: glucose → glucose-6-phosphate (G6P).
Hexokinase: broad specificity, low Km, not insulin-dependent.
Glucokinase (liver): liver-specific, higher Km, induced by insulin, reduced in starvation/diabetes.
Fates of G6P:
Glycogenesis: glycogen storage (liver and skeletal muscle).
Glycogenolysis: glycogen breakdown to release glucose.
Glycolysis: breakdown to pyruvate and lactate for energy.
Interconversion with other macromolecules:
Gluconeogenesis: lactate or non-glucose precursors → glucose.
Glucose → fats via acetyl-CoA.
Fat to glucose: glycerol yields limited glucose via acetyl-CoA conversion to pyruvate (reversible steps limited by biochemistry).
Lipids and lipid metabolism:
Major lipid classes: fatty acids and derivatives, neutral fats (triglycerides), phospholipids, sterols.
Triglycerides: three fatty acids + glycerol; major energy stores.
Fatty acids: even-numbered carbons; saturated (no double bonds) vs unsaturated (one or more double bonds).
Phospholipids: structural components of membranes; precursors for signaling molecules.
Lipid transport and lipoproteins:
Lipids are water-insoluble; transport via lipoprotein complexes.
Lipoproteins have a hydrophobic core (triglycerides, cholesteryl esters) and an outer layer of phospholipids, cholesterol, and apolipoproteins.
Major classes: chylomicrons, VLDL, IDL, LDL, HDL; densities inversely related to lipid content.
Lipoprotein metabolism pathways:
Exogenous (intestinal absorption of dietary lipids) and endogenous (liver-derived lipids transported to tissues).
Lipoprotein lipase (LPL) and LDL receptors play key roles; reverse cholesterol transport via HDL.
Brown fat and energy expenditure (brief):
Brown adipose tissue is a smaller fraction of total fat; more abundant in infants; multiple anatomical sites in adults; extensive sympathetic innervation.
Intercellular Communication and Signaling
Intercellular signaling modes:
Endocrine: hormones travel via blood/lymph to distant targets.
Paracrine: local diffusion of mediators to nearby cells.
Autocrine: mediators act on the releasing cell’s receptors.
Juxtacrine: require direct cell–cell contact.
Synaptic (neural): neurotransmitters released at synapses across narrow clefts.
Gap junctions: direct cytoplasmic channels allowing rapid exchange of ions and small solutes between adjacent cells.
Cell surface receptors and signaling mechanisms:
Receptors can be downregulated or upregulated depending on messenger levels (desensitization/adaptation).
Four major transmembrane signaling mechanisms:
Ligand-gated ion channels (ion flow alters membrane potential).
G-protein-coupled receptors (GPCRs): activate heterotrimeric G-proteins, leading to second messenger cascades.
Enzyme-linked receptors: enzymatic activity or association triggers intracellular signaling.
Intracellular receptors: receptors located inside the cell that respond to lipophilic ligands.
Second messengers and kinases:
First messengers: extracellular ligands (hormones, neurotransmitters).
Second messengers: intracellular signals (cAMP, IP₃, DAG, Ca²⁺, NO) amplify and relay the signal.
cAMP pathway: activation of adenylate cyclase → cAMP → PKA activation → phosphorylation of target proteins; PKA may enter nucleus to phosphorylate CREB (cAMP response element-binding protein) to regulate gene transcription.
IP₃ and DAG: IP₃ triggers Ca²⁺ release from ER; DAG activates protein kinase C (PKC) and may activate receptor-operated Ca²⁺ channels, further increasing cytosolic Ca²⁺.
cGMP pathway: nitric oxide (NO) stimulates guanylate cyclase to increase cGMP; PKG mediates downstream effects; important in vascular signaling and other processes.
Ca²⁺ as a second messenger:
Stored in ER and other organelles; released via ligand-gated channels (IP₃ receptors, ryanodine receptors) or voltage-gated channels; Ca²⁺-binding proteins propagate downstream effects in contraction, secretion, etc.
G-proteins and GPCRs:
GPCRs have seven transmembrane helices; activation leads to GDP → GTP exchange on the α-subunit and dissociation of Gα from Gβγ to regulate effectors.
GPCRs are major drug targets due to their diversity and central signaling role.
Nuclear and cytoplasmic receptors:
Some ligands bind intracellular receptors and directly modulate transcription (e.g., steroid hormones, thyroid hormones).
Vesicular Trafficking and Membrane Transport
Endomembrane system and trafficking overview:
Rough ER synthesizes proteins destined for secretion or membranes; ribosomes attach to cytoplasmic side.
Golgi apparatus modifies, sorts, and packages proteins and lipids for delivery to lysosomes, plasma membrane, or secretion.
Vesicles shuttle cargo between ER, Golgi, lysosomes, and plasma membrane; vesicular trafficking is regulated by small GTPases and SNARE proteins (v-SNAREs and t-SNAREs).
Exocytosis:
Secretory vesicles are targeted to the plasma membrane; docking via SNARE complex; fusion releases vesicle contents outside the cell; membrane remains intact; Ca²⁺-dependent.
Endocytosis:
Uptake of material via membrane invagination and vesicle formation; types include phagocytosis (engulfment of large particles) and pinocytosis (uptake of fluid and solutes).
Receptor-mediated endocytosis concentrates cargo via clathrin-coated pits.
Vesicular transport pathways:
Secretory pathway: ER → Golgi → vesicles → plasma membrane or lysosomes.
Recycling pathway: endocytosis and recycling of membrane components.
Transport proteins and channels:
Passive permeability: small nonpolar molecules (O₂, N₂) diffuse easily; water uses aquaporins.
Facilitated diffusion: carrier proteins transport ligands down gradients without energy; some transporters can move substances against gradients (active transport).
Primary active transport: uses ATP hydrolysis (e.g., Na⁺/K⁺ ATPase).
Secondary active transport: uses energy from the gradient of another ion transported by an initial primary active pump (e.g., Na⁺-coupled transport).
Transport modes (examples):
Uniport: single-substance transport.
Symport: cotransport of two substances in the same direction (e.g., Na⁺-glucose symport).
Antiport: exchange of substances in opposite directions.
Ion channels and gating:
K⁺, Na⁺, Ca²⁺, Cl⁻ channels with various gating mechanisms:
Voltage-gated
Ligand-gated
Mechanosensitive
Channel permeability contributes to rapid changes in membrane potential and signaling.
Cytoskeleton, Organelles, and Cell Structure
Cytoskeleton components and roles:
Microtubules (tubulin): tracks for organelle/vesicle transport; form mitotic spindle during cell division; bidirectional cargo transport.
Intermediate filaments: structural support; vary by cell type (e.g., vimentin in fibroblasts; cytokeratin in epithelia); provide mechanical resilience.
Microfilaments (actin): support, microvilli formation, lamellipodia for movement; interact with integrins in focal adhesions; serve as tracks for motors in some contexts.
Centrosomes and microtubule organization:
Centrosome near nucleus; composed of two centrioles and pericentriolar material; centrioles have nine triplets of microtubules.
Act as microtubule-organizing centers (MTOCs); essential for spindle formation during mitosis.
Nucleus and nucleic acids:
Nucleus contains chromosomes; nuclear envelope with pores; nucleolus as site of ribosome synthesis; chromatin = DNA + proteins.
Endoplasmic reticulum and ribosomes:
Rough ER: ribosomes on cytosolic face; synthesizes proteins for secretion and membranes; initial folding and disulfide bond formation.
Smooth ER: lacks ribosomes; lipid synthesis and detoxification; sarcoplasmic reticulum (in muscle) stores/releases Ca²⁺ for signaling and contraction.
Golgi apparatus:
Polarized with cis (ER-proximal) and trans (plasma membrane-proximal) faces; site for glycosylation; sorting and packaging for delivery.
Lysosomes:
Acidic lumen (pH ~5.0); contain 40+ hydrolytic enzymes; digest extracellular material and worn-out organelles; safety via acidic pH to limit damage if rupture occurs.
Peroxisomes:
Contain oxidases and catalases; involved in lipid metabolism and detoxification; numerous enzymes for anabolic/catabolic reactions; targeting signals direct proteins to peroxisomes.
The Nuclear and Genetic Machinery
DNA structure and replication:
DNA consists of two antiparallel strands forming a double helix; A pairs with T; G pairs with C.
Replication is semi-conservative; each daughter cell receives one old and one new strand; DNA polymerases synthesize new strands.
Gene expression and regulation:
All nucleated somatic cells contain the entire genome; transcription is regulated by cell type, location, and time.
Eukaryotic transcription and translation involve processing of mRNA; ribosomes translate mRNA into polypeptides.
Chromosomal basics:
Ploidy: Diploid (2n) normally; Tetraploid (4n) just before division; aneuploidy is abnormal chromosome number, common in cancer.
Meiosis vs mitosis:
Mitosis: somatic cell division; maintains chromosome number; creates two identical daughter cells.
Meiosis: germ cell division; reduces chromosome number by half; fertilization restores diploidy in zygote.
Central Dogma, RNA, and Protein Synthesis in Cells
RNA types and roles:
mRNA: carries coding sequence from DNA to ribosome.
tRNA: delivers amino acids to ribosome during translation.
rRNA: structural/enzymatic component of ribosomes.
Translation and post-translational modifications:
Ribosome reads mRNA codons; tRNA brings matching amino acids; peptide bonds form to build polypeptides.
Post-translational modifications tune protein activity, localization, stability.
Energy Use in Cells: Metabolism and ATP Allocation
Overview of energy transduction: substrates feed into glycolysis, TCA cycle, and oxidative phosphorylation; ATP generated is allocated to biosynthetic and transport tasks.
Key pathways and connections:
Carbohydrate metabolism feeds acetyl-CoA for lipid synthesis; amino acids provide substrates for gluconeogenesis and energy production.
Lipids provide dense energy storage in adipose tissue; β-oxidation generates acetyl-CoA for the TCA cycle.
Major Cellular Pathways and Organellar Interactions
Golgi and vesicular traffic:
Proteins synthesized in the RER are trafficked through Golgi for modification and sorting; vesicles carry cargo to lysosomes, plasma membrane, or secretion.
Vesicle targeting and fusion are regulated by SNARE proteins (v-SNAREs and t-SNAREs) and small GTPases.
Endocytosis and exocytosis:
Exocytosis releases secretory products; endocytosis internalizes external material; both are essential for secretion, nutrient uptake, and receptor turnover.
Apoptosis vs necrosis:
Apoptosis: programmed cell death under genetic control; caspases (cysteine proteases) are activated; features include DNA fragmentation, chromatin condensation, membrane blebbing; debris phagocytosed without provoking inflammation.
Necrosis: cell lysis due to injury; inflammation occurs due to release of cellular contents.
Receptors and Signal Transduction in Cells
Four major transmembrane signaling mechanisms (reiterated):
Ligand-gated ion channels
G-protein-coupled receptors (GPCRs)
Enzyme-linked receptors
Intracellular receptors (nuclear receptors)
First and second messengers:
First messengers are extracellular ligands (hormones, neurotransmitters).
Second messengers (cAMP, cGMP, IP₃, DAG, Ca²⁺, NO) amplify intracellular signaling.
cAMP pathway details:
Gs increases adenylate cyclase activity → ↑cAMP → activates PKA → phosphorylation of target proteins; CREB activation may alter gene transcription.
cGMP pathway details:
NO stimulates soluble guanylate cyclase to produce cGMP; cGMP activates PKG and modulates ion channels and protein activity.
Important features:
Downregulation/upregulation of receptors modulate cellular responsiveness.
Second messengers coordinate short-term and long-term cellular responses (enzyme activity, exocytosis, transcriptional regulation).
Intercellular Junctions and Communication in Tissues
Tight junctions (zonula occludens):
Located at apical margins of epithelial cells; seal paracellular space, control leakiness, and maintain cell polarity by restricting lateral diffusion of membrane proteins.
Molecular components: occludin, claudins, junctional adhesion molecules, and cytosolic plaque proteins.
Zonula adherens and focal adhesions:
Zonula adherens: basal to tight junctions; cadherins link cells and connect to actin filaments.
Focal adhesions: anchor cells to basal lamina; link to actin cytoskeleton; dynamic structures involved in migration.
Desmosomes and hemidesmosomes:
Desmosomes: patch-like junctions with cadherins; connect intermediate filaments of adjacent cells.
Hemidesmosomes: half-desmosomes that attach cells to extracellular matrix via integrins; connect to intermediate filaments inside the cell.
Gap junctions:
Cytoplasmic tunnels formed by connexons; allow passage of ions, sugars, amino acids (< ~1000 Da) and signaling molecules; enable rapid electrical and chemical coupling between cells.
Receptors, Signaling, and Clinical Relevance
Major CAM families and adhesion:
Integrins (heterodimers) bind to extracellular matrix and ligands; connect to cytoskeleton; mediate signaling and mechanical stability.
Immunoglobulin (Ig) superfamily adhesion molecules; cadherins (Ca²⁺-dependent) mediate homophilic cell–cell adhesion; selectins mediate leukocyte-endothelial interactions.
Intercellular communications recap (diagrammatic):
Juxtacrine signaling requires direct contact; paracrine and autocrine use diffusion in interstitial fluid; endocrine uses circulation; synaptic uses neurotransmitter diffusion across synaptic cleft.
Receptors and ligands:
Downregulation/upregulation balance receptor availability; effects depend on receptor density and signaling context.
Practical Illustrations and Selected Figures (from the Transcripts)
Isotonic solutions and tonicity examples:
0.9% saline is isotonic with plasma; no net water movement across red blood cell membranes.
5% glucose is initially isotonic but becomes hypotonic as glucose is metabolized, drawing water into cells.
Donnan effect and cell volume:
Non-diffusible intracellular proteins shift ionic balance and water distribution; Na⁺/K⁺ ATPase counters osmotic swelling.
Membrane potentials and NK/Nernst principles:
Equilibrium potentials for each ion are determined by gradients and charge; resting membrane potential emerges from the balance of K⁺ leak and Na⁺/K⁺ ATPase activity.
Key numerical references:
Plasma osmolality contributors: ~270 mOsm/L from Na⁺ and accompanying anions; glucose ~5 mOsm/L; urea ~5 mOsm/L.
Typical resting potential: ~−70 mV; EK ≈ −90 mV; ECl ≈ −70 mV; ENa ≈ +60 mV.
Na⁺/K⁺ ATPase: 3 Na⁺ out, 2 K⁺ in per ATP hydrolyzed; electrogenic contribution to membrane potential.
Core Formulas and Key Relationships (LaTeX)
pH definition:
ext{pH} = -\,\log_{10}([\mathrm{H^+}])
Henderson–Hasselbalch:
\text{pH} = \text{p}K_a + \log\left(\frac{[\mathrm{A^-}]}{[\mathrm{HA}]}\right)
Carbonic acid–bicarbonate system (reversible):
\mathrm{CO2 + H2O \rightleftharpoons H2CO3 \rightleftharpoons H^+ + HCO_3^-}
Nernst equation (ion equilibrium potential; simplified at 37°C):
E{ion} = \frac{RT}{zF} \ln \left(\frac{[\text{ion}]{\text{out}}}{[\text{ion}]{\text{in}}}\right) \\approx \frac{61.5\ \text{mV}}{z} \log{10}\left(\frac{[\text{ion}]{\text{out}}}{[\text{ion}]{\text{in}}}\right)
Na⁺/K⁺ ATPase stoichiometry:
\text{Na}^+/\text{K}^+\ \text{ATPase}: 3\;\text{Na}^+\;\text{out},\ 2\;\text{K}^+\;\text{in} \\text{per ATP hydrolysis}
Energy partition (illustrative):
\%\text{ATP usage} = {27, 24, 9, 6, 5, 3}\%\quad \text{(protein synthesis, Na⁺/K⁺ ATPase, gluconeogenesis, Ca²⁺ ATPase, myosin ATPase, ureagenesis)}
Notes for Exam Preparation
Understand how energy production integrates substrate oxidation, electron transport, and ATP synthesis; relate to tissue energy needs (e.g., muscle vs neurons).
Be able to compare compartments (ICF vs ECF) and explain why diffusion/osmosis determine fluid distribution and edema risk.
Explain pH control mechanisms: buffers, respiratory compensation, and renal compensation; apply Henderson–Hasselbalch to buffer systems (bicarbonate, phosphate, protein buffers).
Describe membrane potential generation and maintenance, including roles of K⁺ leak channels and Na⁺/K⁺ ATPase.
Memorize core organelle functions and their contributions to metabolism and protein processing (RER, SER, Golgi, lysosomes, peroxisomes, mitochondria).
Distinguish carbohydrate, lipid, and protein metabolism pathways; know key entry points of amino acids into energy metabolism (glucogenic vs ketogenic) and the overall fate of glucose in glycolysis, gluconeogenesis, and glycogen storage.
Recognize signaling pathways (cAMP, IP₃/DAG, Ca²⁺, cGMP) and the roles of GPCRs, enzyme-linked receptors, and nuclear receptors in cellular responses.
Understand the differences between apoptosis and necrosis, including the role of caspases and the implications for inflammation and tissue remodeling.
Be familiar with the exocytic and endocytic pathways and how vesicular trafficking enables secretion, receptor turnover, and nutrient uptake.
References
Ganong’s Review of Medical Physiology, 26th Edition (Kaye S. De Leon-Nolasco; Chapter 1–2 references in the transcript).
Barrett, K. E., Barman, S. M., Brooks, H. L., & Yuan, J. (2019). Ganong’s review of medical physiology (26th ed.). McGraw-Hill Education.