Textbook reference: Chapter 1-3 Ganong's Review of Medical Physiology

% of MCQ Matrix: 5% 

Definitions

Doonan effect: 2 diffusible ions are predictably distributed across a membrane that has a non-diffusible ion on side A [i.e. a large negatively charged protein, which will attract positive ions (like Na+) and repel negative ions (like Cl-)]. As a result, more positive ions will stay on side A compared to side B. Since side A has more dissolved(and osmotically active) particles, water moves to side A by osmosis.

Doonan-Gibbs equation: [Na+]A×[Cl-]A=[Na+]B×[Cl-]B i.e. The product of diffusible positive and negative ion concentrations becomes equal on both sides. This means when one side has trapped negative proteins, the ion concentration becomes uneven, but in a predictable way. Note anion and cation must have same valence for this to be true.

Fick’s law: diffusion is proportional to cross sectional area (A) + concentration gradiency, and inversely proportional to boundary thickness.

Diffusion: Net flux of solute particles from areas of high concentration to low concentration

Main consequences of the Doonan effect:

Main consequences:

1)Water moves towards side with more trapped proteins. Therefore, if it were not for Na,K, ATPase pumps on cell membranes, cells would swell and rupture all the time. 

2)There is an electrical difference across membranes at equilibrium, due to asymmetrical ion distribution.

3) Donnan effect on ion movement across the capillary wall because plasma protein>interstitial fluid protein.

Describe the Na/K ATPase pump in detail

Na/K ATPase catalyses the hydrolysis of ATP to ADP, and uses this energy to extrude 3x Na+ FROM the cell, and take 2x K+ INTO the cell, for each molecule of ATP that is hydrolysed.

  • Electrogenic pump
  • Coupling ration 3:2 (3x Na OUT for every 2x K+ IN)
  • Active transport of Na and K accounts for 24% of energy utilised by cells, and in neurons it accounts for 70%

How it works: Na binds to alpha subunit + ATP binds-->ATP converted to ADP-->phosphate transferred to Asp 376-->change in configuration of the protein-->Na extruded into ECF-->K binds extracellularly, de-phosphorylating the alpha subunit-->alpha subunit returns to its original conformation, releasing K into the cytoplasm

Structure:

  • Composed of 3 subunits assembled in a 1:1:1 stoichiometry; alpha, beta and gamma
  • Na/K transport occurs through the alpha subunit. The alpha subunit has intracellular Na and ATP binding sites. The expression of the alpha subunit is tissue-specific. The apha-2 isoform is predominant in muscle and heart tissue.
  • The beta subunit is a glycoprotein. The beta subunit its widely distributed but is absent in certain astrocytes. Vestibular cells of the inner ear and glycolytic fast twitch muscles.
  • The amount of Na normally found in cells is not enough to saturate the pump

What increases/decreases its activity:

  • Thyroid hormones increases pump activity by a genomic action to increase the formation of Na, K, ATPase molecules.
  • Insulin increases pump activity.
  • Dopamine in the kidney inhibits the pump by phosphorylating it, causing naturesis.
  • Actively inhibited by Ouabain and related digitalis glycosides

How is temperature regulated? Why does fever occur?

Fever = ↑ hypothalamic set-point('thermostat has been reset'), mediated largely by PGE₂ in response to pyrogenic cytokines (such as IL-1, IL-6 and TNF-α).

Infection/inflammation→ monocytes, macrophages, Kupffer cells release of pyrogenic cytokines → PGE₂ → hypothalamic set-point ↑ (in the preoptic area of the hypothalamus) → vasoconstriction/shivering/increased thermogenesis → fever

Paracetamol, Ibuprofen and Aspirin all reduce fever by ↓ COX activity → ↓ PGE₂ → ↓ hypothalamic set-point → ↓ fever

How is Malignant Hyperthermia fundamentally different from fever?

Malignant hyperthermia

  • NOT an increase in ‘set point’ , but rather uncontrolled heat production
  • Anaesthetic trigger-->existing mutation in the gene coding for the ryanodine receptor leads to excess calcium released during muscle contraction triggered by stress-->muscle contractures, skeletal-muscle hypermetabolism, increase in heat production in muscle

What are the determinants of plasma glucose level?

Glucose enters blood from:

Gut → dietary glucose

Liver → glycogenolysis + gluconeogenesis [Liver = major regulator of blood glucose]

Kidney → gluconeogenesis [Kidney = increasingly important during prolonged fasting]

Glucose leaves blood through:

Cellular uptake/utilisation

  • Skeletal muscle = major glucose consumer but does NOT release free glucose into blood because it lacks glucose-6-phosphatase.

Glycogen synthesis by the liver: ↑ insulin → glucose uptake/storage → ↓ plasma glucose.

Conversion to fat by the liver: glucose → pyruvate → acetyl-CoA → fatty acids → triglycerides = lipogenesis

Urinary loss when plasma glucose exceeds the renal threshold

 

Insulin LOWERS BGL, whereas glucagon + adrenaline + cortisol + growth hormone INCREASES BGL

Describe the second messenger systems with examples

A second messenger is an intracellular signalling molecule that transmits and amplifies a signal from a cell-surface receptor to intracellular targets. The first messenger is usually an extracellular hormone or neurotransmitter (e.g. adrenaline). Because many of these molecules cannot cross the lipid membrane, they activate membrane receptors, which generate second messengers inside the cell.

GPCR; G proteins, calcium and cAMP

Ligand → GPCR → G protein → adenylyl cyclase → cAMP → PKA → cellular response

  • Gs (e.g. β₁, β₂, β₃ adrenergic receptors) → stimulates adenylyl cyclase → ↑ cAMP → ↑ PKA
    • Cholera toxin locks Gs in the “ON” position → adenylyl cyclase stays active → ↑↑ cAMP → massive Cl⁻ and water secretion into the intestine → watery diarrhoea.
  • Gi (e.g. α₂ adrenergic receptor ) → inhibits adenylyl cyclase → ↓ cAMP → ↓ PKA
    • Pertussis toxin locks Gi in the “OFF” position → Gi can no longer inhibit adenylyl cyclase → ↑ cAMP → increased respiratory secretions 

Ligand → GPCR → Gq → phospholipase C (PLC) → PIP₂ → IP₃ + DAG

  • IP₃ → releases Ca²⁺ from the endoplasmic reticulum
  • DAG + Ca²⁺ → activates protein kinase C (PKC)
  • e.g. α₁, M₁, M₃, H₁

cGMP

Ligand → guanylyl cyclase → cGMP → protein kinase G (PKG) → cellular response

  • Nitric oxide (NO)→ Activates soluble guanylyl cyclase→ ↑ cGMP → smooth muscle relaxation → vasodilation
  • ANP/BNP→ Bind membrane guanylyl cyclase receptors→↑ cGMP→ promotes natriuresis and vasodilation
  • cGMP is important in vision in both rod and cone cells

Tyrosine Kinase

Ligand → RTK dimerisation → autophosphorylation → intracellular signalling pathways → cellular response

  • e.g. Insulin

JAK/STAT

Ligand → receptor → JAK activation → STAT phosphorylation → STAT dimerisation → nucleus → gene transcription

  • e.g. Growth Hormone

What is secondary active transport? How else does transport occur across the cell membrane?

Primary active transport uses ATP directly; secondary active transport uses the energy of an ion gradient generated by primary active transport

Two main types:

1) Symport (both substances move in the same direction)

  • In lumen of small intestine
  • Example: SGLT (Na-glucose cotransporter)
  • Transports glucose into cell only if Na binds to the protein and is transported into the cell at the same time. Na is then actively transported out of the mucosal cell into the ECF

2) Antiport (counter-transport)

  • In the membranes of cardiac muscles
  • Example: Sodium-Calcium Exchanger; 3 Na⁺ move INTO the cardiac myocyte ↔ 1 Ca²⁺ moves OUT, helping cardiac muscle cells relax after contraction

What are the major components of the immune system

INATE

RAPID, NON-SPECIFIC

  • Antigens are recognised by the innate system through 'toll-like receptors', which are 'pattern recognition receptors'
  • Several of the cells in the innate system are 'antigen presenting cells' which literally present an antigen (or part thereof) to another cell for targeted destruction. These include Dendritic cells and Macrophages. 
  • Opsonisation is the coating of bacteria by IgG and/or complement, making them ‘tasty’ to phagocytes and flagging them for destruction
  • Neutrophils; 6h half life.
    • Bacteria invade>bone marrow stimulated to make neutrophils>chemokines released>selectins attract them to endothelial surface>roll along it>diapedesis to enter e.g. GI tract>opsonised bacteria bind to neutrophil cell membrane>phagocytosis, degranulation (defensins and toxic O2 metabolites, myeloperoxidase), release of NETS to bind and kill microbes and act as a physical barrier to pathogens
  • Eosinophils; stimulates IL-3, IL-5 and GM-CSF, abundant in mucosa of GI tract/urinary tract/resp tract where they defend against parasites
  • Basophils; contain histamines, bind IgE, involved in allergic reactions
  • Mast cells; heavily granulated (proteoglycans, histamine), degranulate when allergens bind to IgE, defend against parasites. Marked mast-cell degranulation leads to anaphylaxis.
  • Macrophages/Monocytes; 72h half life, act as an antigen presenting cell, e.g. Kuppfer cell in liver, pulmonary alveolar macrophages, microglia in the brain
  • Natural Killer cells; kill cells ( with cytotoxic granules) which have low/absent MHC-I
  • Platelets; non-nucleated, pinched of part of megakaryocyte, contains 2 granules; dense granules and alpha granules, contains von-willenbrand factor.
    • Thrombopoietin ( produced by liver + kidneys) binds platelets, but it also stimulates their production; this means that when circulating plts are low there is less TPO bound, and more circulating TPO available to stimulate the production of platelets.
  • Chemotactic agents; C5a, leukotrienes, and polypeptides from lymphocytes, mast cells and basophils
  • Complement (see below)

ADAPTIVE/ACQUIRED

SLOWER, SPECIFIC, MEMORY

  • Common lymphoid progenitor→B cell, T cell and NK cell(part of innate)
  • Humoral immunity; immunoglobulins/B cells
    • Naïve B cell is developed in the BONE MARROW, matures in lymph and spleen
    • IgM = first responder, large pentamer, complement activation.
      IgG =       main long-term antibody(most abundant), crosses placenta, strong secondary immune response.
    • IgA; secretory/mucosal immunity, protects the gut. Antigens are taken up by M cells in gut→moved to Peyers Patches of lymphoid tissue in gut→plasma B cells learn to produce IgA→epithelial cells produce a secretory component which binds to IgA allowing it to ‘taxi’ across the epithelial cell. Because IgA is secreted into the breast milk it also account for the immune protection that is conferred by breastfeeding of infants which immune systems are otherwise immature.
    • IgE: parasite defence, involved in hypersensitivity/allergic reaction
  • Cellular immunity; T cells
    • T cells mature in the THYMUS
    • CD4+ = helper T cells, pairs with MHC II= secretes cytokines(generally paracrine)
    • CD8+= cytotoxic T cell, pairs with MHC I (which is found on all nucleated cells)= direct killers
  • Chemokines: cytokines which guide immune effector cells to areas of inflammation

Describe the classical versus alternate complement pathway

There are 3 Pathways of Complement Activation

  1. Classical - triggered by antigen-antibody(IgG/IgM) complex
  2. Alternative - triggered by direct binding of antigen (innate immunity)
  3. Lectin - when lectins binds mannose on bacteria

All pathways lead to C3 splitting to C3a and C3b

  • C3b opsonizes organisms and initiates the formation of membrane-attack complex - MAC
  • C3b splits C5 into C5a + C5b
    • MAC formation is initiated by C5b; formed by polymerized C9 molecules
    • C3a and C5a are pro-inflammatory mediators 

What are the clinical implications of complement deficiencies?
  • C3 deficiency → Recurrent severe bacterial infections, because C3 is central to both pathways
  • C5–C9 deficiency → patient can get recurrent Neisseria infections, because the MAC is important for killing Neisseria.
  • C1 esterase inhibitor deficiency → hereditary angioedema: low C4, recurrent non-urticarial angioedema.
  • C1/C2/C4 deficiencies → can be associated with SLE-like disease.