General and Molecular Basis of Medical Physiology Flashcards
What proportion of body weight is total body water?
60%
40% of total body weight is ICF
20% of total body weight is ECF
What are the constituents of ECF volume?
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
What is Total blood volume?
Total blood volume = blood plasma + blood cell volume
What is the difference in K+ and Na+ in the ICF and ECF compartments?
ICF is high in K+ and low in Na<span>+ </span>
ECF is high in Na<strong>+</strong> and low in K+
What are the major anions in ECF?
Cl- and HCO3-
What are the major anions in ICF?
Phosphate and protein
The proccess by which small non-polar molecules passively cross a membrane down their electrochemical gradient
Diffusion
What are aquaporins?
A group of membrane proteins that transport non-ionised molecules across membranes
Give 3 types of endocytosis
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
What type of transport is thought to be responsible for regulation of cholestrol absorption?
Calveoli-mediated transport
What is secondary active transport?
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
Describe the structure of the Na+/K+ ATPase
- 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
What is Fick’s law?
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
What is the Gibbs-Donnan effect?
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]
What are 3 physiological consequences of the Gibbs-Donnan effect?
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
What is the Nernst equation?
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
Give 4 ways by which chemical messengers are passed between cells?
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
By what 4 mechanisms can chemical messengers act on a receptor?
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
What are the most common second messenger systems?
1) Calcium
2) G-proteins
3) IP3 and DAG
4) cAMP
5) cGMP
Describe the role of calcium as a second messenger in cells
- 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
Describe the structure of a G-protein-coupled receptor
- 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
Give some examples of ligands for G-protein coupled receptors
Neurotransmitters eg epinephrine, dopamine, histamine, acetylcholine
Tachykinins eg substance P, neurokinin A, neuropeptide K
Angiotensin 2, vasopressin, oxytocin
Glycoprotein hormones eg TSH, FSH, LH
Describe the role of IP3 as a second messenger
- 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
Describe the role of cAMP as a second messenger
- 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
Describe the mechanism of cGMP signalling
cGMP is created by guanalyl cyclase in response to NO > activates protein kinase G (PKG) > causes myosin light chain dephosphorylation > vasodilation
What is pH?
The pH is the logarithm to the base 10 of the reciprocal of the hydrogen ion concentration
pH = -log [H+]
What is the Henderson Hasselbach equation?
pH = pKa + log ([A-]/[HA])
What is a buffer?
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+
What is the osmolal concentration?
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 1.86oC
What is the osmolarity?
The number of osmoles per litre of solution
What is the osmolality?
The number of osmoles per kilogram of solvent (calculated considering the mass of a solution)
Is osmolarity or osmolality affected by temperature and pressure
Osmolarity is affected by temperature and pressure but osmolality is not
What is the formula used to calculate plasma osmolarity ?
Osmolarity = 2[Na+] + 0.055[glucose] + 0.36[BUN]
What is the definition of osmotic pressure?
The pressure necessary to prevent solvent migration
What is tonicity?
The term used to describe the osmolality of a solution relative to plasma
What are electrical equivalents?
1 eq = 1 mole of an ionised substance divided by its valence
What is the significance of cholera and pertussis on cell signalling?
Cholera toxin prolongs Gs activity by preventing GTP autocatalysis
Pertussis toxin inhibitis Gi activity
Both result in increased intracellular cAMP
What are the 3 pathways for primary messengers to alter transcription of cells?
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
What are the 3 groups of growth factors?
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
Describe the mechanism of tyrosine kinase signalling with EGF and PDGF
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
What are the 2 types of immunity?
Innate immunity
Acquired immunity
What are the key components of the innate immune system?
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.
What are the components of the adaptive immune system?
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.
What is meant by the terms humoral and cell-mediated immunity?
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
What are the different types of B cells?
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
How do T cells differ to B cells?
- 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
What are the different types of antigen presenting cell
- 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
What are the functions of immunoglobulins?
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
Describe the structure of immunoglobulins
- 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
Which Ig is a pentamer?
IgM is a pentamer
Which Ig are involved in complement activation?
IgG, IgM
What are the different types of Ig?
What are cytokines?
Paracrine molecules that regulate immune responses
What secretes TNFalpha
Macrophages
NK cells
T and B cells
Mast cells
What secretes IL1, IL2 and IL4?
IL1 - Macrophages
IL2 - T helper cells
IL4 - T helper cells
