General and Molecular Basis of Medical Physiology

Question 1

What proportion of body weight is total body water?

Answer 1

60%

40% of total body weight is ICF

20% of total body weight is ECF

Question 2

What are the constituents of ECF volume?

Answer 2

ECF volume is 20% of total body weight (or 1/3 of total body water)

15% of total body weight is interstitial fluid

5% of total body weight is blood plasma

Question 3

What is Total blood volume?

Answer 3

Total blood volume = blood plasma + blood cell volume

Question 4

What is the difference in K⁺ and Na⁺ in the ICF and ECF compartments?

Answer 4

ICF is high in K⁺ and low in Na^{<span>+ </span>}

ECF is high in Na^{<strong>+</strong>} and low in K⁺

Question 5

What are the major anions in ECF?

Answer 5

Cl^- and HCO3^-

Question 6

What are the major anions in ICF?

Answer 6

Phosphate and protein

Question 7

The proccess by which small non-polar molecules passively cross a membrane down their electrochemical gradient

Answer 7

Diffusion

Question 8

What are aquaporins?

Answer 8

A group of membrane proteins that transport non-ionised molecules across membranes

Question 9

Give 3 types of endocytosis

Answer 9

1) Phagocytosis - bacteria and dead tissue engulfed by cells
2) Pinocytosis - “Cell drinking” invagination of the cell mrmbrane to form a pocket which then pinches off into the cell to form a vesicle
3) Clathrin mediated - Clathrin accumulates in indentations on the cell surface and facilitates endocytosis of receptors and ligands

Question 10

What type of transport is thought to be responsible for regulation of cholestrol absorption?

Answer 10

Calveoli-mediated transport

Question 11

What is secondary active transport?

Answer 11

When the active transport of Na+ generates an electrochemical gradient, the energy in this gradient is used to transport another molecule across the membrane

Counter-transport eg The Na+/Ca2+ counter-transport system in myocytes by the NCX(Na/C exchange transporter

Co-transport eg Na+, glucose co-transport in the proximal tubule and the GIT

Question 12

Describe the structure of the Na⁺/K⁺ ATPase

Answer 12

• alpha and beta subunits which are both transmembrane
• alpha subunit has intracellular binding sites for Na+ and ATP, and extracellular binding sites for K+
• beta subunit has no binding sites

Question 13

What is Fick’s law?

Answer 13

The magnitude of diffisuion tendency is proportional to the concentration gradient and cross sectional area across which diffusion takes place and is inversely proportional to the thickness of the membrane

Question 14

What is the Gibbs-Donnan effect?

Answer 14

Describes the observed phenomenon whereby two diffusible ions are predictably distributed across a membrane which has a non-diffusble ion on one side.

The diffusible ions distribute themselves such that at equilibrium their concentration ratios are equal

ie [K⁺_x][Cl^-_x]=[K⁺_y][Cl^-_y]

Question 15

What are 3 physiological consequences of the Gibbs-Donnan effect?

Answer 15

1) Normal cell volume and pressure depend on the Na⁺/K⁺ ATPase because there are more osmotically active particles in cells than interstitial fluid (protein)
2) At equilibrium the distribution of permeant ions across the membrane is assymetric - an electrical difference exists across the membrane. Its magnitude can be determined by the Nernst equation
3) Since there are more proteins in plasma than interstital fluid, there is a Donnan effect on ion movement across the capillary wall

Question 16

What is the Nernst equation?

Answer 16

The Nernst equation calculates the equilibrium potential based on the charge of the ion (its valence) and its concentration gradient across the membrane.

Equilibrium potential is the electrical potential difference across the cell membrane that exactly balances the concentration gradient for an ion

Question 17

Give 4 ways by which chemical messengers are passed between cells?

Answer 17

1) Gap junctions - allow transfer of chemical messengers directly to neighbouring cell
2) Neural communication (synaptic) - when neurotransmitters are released into a synaptic junction from nerve cells
3) Paracrine communication - cell products diffuse into the ECF and affect cells some distance away
4) Endocrine communication - Secretion of hormones and growth factors into circulation allowing them to exert an effect on cells throughout the body

Question 18

By what 4 mechanisms can chemical messengers act on a receptor?

Answer 18

1) Ion channel activation eg Ach acting on nicotinic receptors
2) G protein activation
3) Activation of enzyme activity within the cell eg tyrosine kinase (insulin) or phospholipase C
4) Direct activation of transcription eg steroids/thyroid hormone

Question 19

What are the most common second messenger systems?

Answer 19

1) Calcium
2) G-proteins
3) IP3 and DAG
4) cAMP
5) cGMP

Question 20

Describe the role of calcium as a second messenger in cells

Answer 20

• There is normally an inwardly-directed electrocehmical gradient
• This gradient is maintained by 2 antiports - the Ca²⁺, H⁺ ATPase and the Na⁺/Ca²⁺ antiport (driven by Na+ gradient). Both transport Ca²⁺ out of the cell
• Intracellular increases are brought about by:
  
  • IP3 activing on the IP3 receptors on the ER to release Ca²⁺
  • Increased Ca²⁺ into the cell
• Calcium binds to many intracellular proteins to exert its effects eg troponin, calmodulin, calbindin
• Removal of calcium from the cytosol is against its electrocehmical gradient. SERCA pump back into ER

Question 21

Describe the structure of a G-protein-coupled receptor

Answer 21

• Large hetrotrimeric proteins made up of 3 subunits - a, b and g
• Serpentine receptors which span the membrane 7 times
• The a subunit is bound to GDP
• Upon ligand binding, the protein exchanges GDP for GTP the a subunit dissociates from the b and g subunits
• Both subunits (a and bg) can act as second messengers and have a variety of functions
• GTPase activity converts GTP to GDP resulting in inactivation and reassociation as heterotrimer

Question 22

Give some examples of ligands for G-protein coupled receptors

Answer 22

Neurotransmitters eg epinephrine, dopamine, histamine, acetylcholine

Tachykinins eg substance P, neurokinin A, neuropeptide K

Angiotensin 2, vasopressin, oxytocin

Glycoprotein hormones eg TSH, FSH, LH

Question 23

Describe the role of IP3 as a second messenger

Answer 23

• Ligand binding activates phospholipase C either directly or via the Gg subtype to catalyse the reaction

PIP2—-> IP3 + DAG

• IP3 binds to Ca2+ receptors on the ER to release Ca2+. Ca2+ causes translocation of PKC to the membrane
• DAG stays in the cell membrane and activates PKC
• PKC is an enzyme involved in multiple downstream signalling cascades

Question 24

Describe the role of cAMP as a second messenger

Answer 24

• cAMP is created by adenylyl cyclase acting on ATP
• Adenylyl cyclase can either be activated or inhibited
• Gs proteins will increase activity whereas Gi proteins will decrease activity
• cAMP activates protein kinase A (PKA) which acts similarly to PKC
• cAMP is inactivated by phosphodiesterases
• Methylxanthines are phosphodiesterase inhibitors and therefore increase cAMP

Question 25

Describe the mechanism of cGMP signalling

Answer 25

cGMP is created by guanalyl cyclase in response to NO > activates protein kinase G (PKG) > causes myosin light chain dephosphorylation > vasodilation

Question 26

What is pH?

Answer 26

The pH is the logarithm to the base 10 of the reciprocal of the hydrogen ion concentration

pH = -log [H⁺]

Question 27

What is the Henderson Hasselbach equation?

Answer 27

pH = pKa + log ([A^-]/[HA])

Question 28

What is a buffer?

Answer 28

A substance that has the ability to bind or release H⁺ in solution thus keeping the pH of the solution relatively constant despite the addition of considerable quantities of acid or base

eg carbonic acid

H₂CO₃ H⁺ + HCO₃^-

Add H+ and the equilibrium shifts to the left, H+ is removed from solution

Add OH^- and the OH^- combines with H⁺ to form H₂O which removes H⁺ from solution and the equation shifts to the right to counter the lack of H⁺

Question 29

What is the osmolal concentration?

Answer 29

The osmolal concentration of a substance in a fluid is measured by the degree to which it depresses the freezing point; with 1 mole of an ideal solution depressing the freezing point 1.86^oC

Question 30

What is the osmolarity?

Answer 30

The number of osmoles per litre of solution

Question 31

What is the osmolality?

Answer 31

The number of osmoles per kilogram of solvent (calculated considering the mass of a solution)

Question 32

Is osmolarity or osmolality affected by temperature and pressure

Answer 32

Osmolarity is affected by temperature and pressure but osmolality is not

Question 33

What is the formula used to calculate plasma osmolarity ?

Answer 33

Osmolarity = 2[Na+] + 0.055[glucose] + 0.36[BUN]

Question 34

What is the definition of osmotic pressure?

Answer 34

The pressure necessary to prevent solvent migration

Question 35

What is tonicity?

Answer 35

The term used to describe the osmolality of a solution relative to plasma

Question 36

What are electrical equivalents?

Answer 36

1 eq = 1 mole of an ionised substance divided by its valence

Question 37

What is the significance of cholera and pertussis on cell signalling?

Answer 37

Cholera toxin prolongs Gs activity by preventing GTP autocatalysis

Pertussis toxin inhibitis Gi activity

Both result in increased intracellular cAMP

Question 38

What are the 3 pathways for primary messengers to alter transcription of cells?

Answer 38

1) Crosses cell membrane and binds to nuclear receptor eg steroid or thryoid hormones
2) Activation of cytoplasmic protein kinases that can move to the nucleus to phosphorylate a latent transcription factor - this is as common end point of signals in the MAP kinase cascade
3) Activation of latent transcription factor in the cytosol which then migrates to the nucleus

Question 39

What are the 3 groups of growth factors?

Answer 39

1) Agents that foster the multiplication or development of various cell types eg insuln like growth factor (IGF), epidermal growth factor (EGF)
2) Cytokines - produced by macrophages and lymphocytes, important in immune system regulation
3) Colony-stimulating factors - regulate proliferation and maturation of red and white blood cells

Question 40

Describe the mechanism of tyrosine kinase signalling with EGF and PDGF

Answer 40

Ligand binds to a tyrosine kinase receptor > dimerisation of 2 similar receptors > partial activation of the intracellular tyrosine kinase domains + cross-phosphorylation to fully activate each other .

One of the pathways activated leads to MAP kinases by the small G protein Ras and eventually to the production of transcription factors in the nucleus

Question 41

What are the 2 types of immunity?

Answer 41

Innate immunity

Acquired immunity

Question 42

What are the key components of the innate immune system?

Answer 42

1) Phagocytes - engulf and destroy harmful organisms
2) Macrophages - efficient phagoytic cells that can leave the circulatory system by moving across capillary vessel walls, can release cytokines to signal/recruit other cells
3) Mast cells - found in mucous membranes and connective tissues - when activated, release cytokines and granules that contain chemical molecules
4) Neutrophils - phagocytic cells that are also classified as granulocytes because they contain granules
4) Basophils - also granulocytes that attack multicellular parasites, release histamine
5) Natural killer cells (NK cells) - destroy infected host cells through specific receptor/antigen presentation
6) The complement system - opsonization, chemotaxis, cell lysis, agglutination
7) Toll-like receptors eg TLR4

• TLR4 binds bacterial lipopolysaccharide and CD14 which initiates intracellular events that activate transcription of genes.
• Bacterial lipopolysaccharide produced by gram negative organisms is the cuase of septic shock.

Question 43

What are the components of the adaptive immune system?

Answer 43

1) B cells - responsible for mediating the production of antigen-specific immunoglobulin directed against invasive pathogens
2) T cells - contain T cell receptors which recognise antigens bound to major histocompatibility complexes (MHCs). Mature T cells can be either helper T cells, cytotoxic T cells and regulatory T cells.

Question 44

What is meant by the terms humoral and cell-mediated immunity?

Answer 44

Humoral - Immunity from serum antibodies produced by plasma cells

Cell-mediated - Immunity mediated by cytotoxic T cells that perforate the membrane/initiate apoptosis in cells presenting an antigen that binds to their cell-surface receptor

Question 45

What are the different types of B cells?

Answer 45

When a B cell encounters an antigen it quickly becomes either a memory B cell or an effector B cell (plasma cell)

Memory B cells express the same membrane bound antibody as the original naive B cell

Plasma B cells produce the same antibody as the B cell but they aren’t membrane bound

B cells also express B cell receptor (BCR) which help with antigen binding, internalisation and processing of the antigen

Question 46

How do T cells differ to B cells?

Answer 46

• T cells express T cell receptors which only recognise antigens that are bound to major histocompatibility complex class 1 and class 2
• T cells also express other receptors - either CD4 or CD8
• There are 3 different types of T cells
  
  • T helper cells - express CD4, help with activation of T cells, B cells and other immune cells
  • Cytotoxic T cells - express CD8 and are responsible for removing pathogens
  • Regulatory T cells - express CD4 and CD25

Question 47

What are the different types of antigen presenting cell

Answer 47

• Dendritic cells - in lymph nodes and spleen
• Langerhans cells- in the skin
• Macrophages and B cells can act as APCs

APCs paritally digest the antigen and then couple them to a major histocompatibility complex (MHC) protein

Question 48

What are the functions of immunoglobulins?

Answer 48

1) Binds and neutralises some protein toxins
2) Prevents attachment of some viruses and bacteria to cells
3) Opsonises bacteria
4) Activates complement via the classical pathway

Question 49

Describe the structure of immunoglobulins

Answer 49

• Comprised of 4 proteins arranged symmetrically and joined together by sulphide bonds
  
  • two identical heavy chains
  • two identical light chains
• The chains are composed of speficic segments
  
  • V (variable) - highly variable
  • D (diversity)
  • J (joining)
  • C (constant) - no variability
• Fab portion is the area involved in antigen binding
• Fc portion is the effector portion that mediates the body’s reaction

Question 50

Which Ig is a pentamer?

Answer 50

IgM is a pentamer

Question 51

Which Ig are involved in complement activation?

Answer 51

IgG, IgM

Question 52

What are the different types of Ig?

Answer 52

Question 53

What are cytokines?

Answer 53

Paracrine molecules that regulate immune responses

Question 54

What secretes TNFalpha

Answer 54

Macrophages

NK cells

T and B cells

Mast cells

Question 55

What secretes IL1, IL2 and IL4?

Answer 55

IL1 - Macrophages

IL2 - T helper cells

IL4 - T helper cells