1
Q
What makes up the cytoskeleton?
A
Microtubules, Intermediate Filaments and Microfilaments.
2
Q
What do microtubules consist of? Where are they found?
A
Polymers of alpha and beta TUBULIN. Found radiating out from Microtubule Organising Centers (MTOCs)
3
Q
What are the sizes of the cytoskeleton filaments?
A
Microtubules - 20nm
Intermediate Filaments - 10-15nm
Microfilaments - 8nm
4
Q
What are the functions of microtubules?
A
- cell shape
- tracks for movement of organelles and vesicles
- component of cilia and flagella (9 + 2 arrangement)
5
Q
Give an example of an Intermediate Filament
A
Nuclear LAMINS form a network on the internal surface of the nuclear envelope (nuclear lamina) involved in stabilising the envelope.
6
Q
What are microfilaments composed of?
A
F-actin (polymer of G-actin)
7
Q
What are the functions of microfilaments?
A
- Associate with adhesion belts in epithelia and endothelia
- Involved in cell shape and movement
- Movement of organelles and vesicles within cells
8
Q
What are the main cell types? What tumours do they form?
A
- Epithelial: Carcinoma
- Mesenchymal cells (cells of connective tissue): Sarcoma
- Haematopoietic (cells of bone marrow and blood cells): Leukaemia and Lymphomas
- Neural (neurones and glia): Neuroblastomas and Gliomas
9
Q
What is the extracellular matrix and what is it composed of?
A
Material deposited by cells which forms the insoluble part of the extracellular environment.
Generally composed of fibrillar proteins (i.e collagens and elastin) embedded in a hydrated gel (proteoglycans).
10
Q
Give an example of where the ECM is poorly organised and highly organised?
A
Poorly - loose connective tissue
Highly - tendon, bone and basal lamina
11
Q
What are the different FORMS of cell-cell junctions?
A
Maculae (spots) and Zonulae (belts)
12
Q
What are the different TYPES of cell-cell junctions?
A
Zonula occludens (Occluding junction / Tight junction) Zonula adherens (Adhesion belt / Adhesion junction) Macula adherens (Spot junction / Desmosome) Macula communicans (Gap junctions) Synapses
13
Q
What are the properties and functions of Tight junctions?
A
- Most apical junction
- Forms a network of contacts, the more elaborate the network, the tighter the signal
- Seals paracellular pathway
- Segregates apical and basolateral membrane (polarity)
14
Q
What are the properties and functions of Adhesion belts?
A
- Form just basal to tight junctions
- Joins actin bundles in neighbouring cells using cadherin molecules
- Controls stability of other junctions
15
Q
What are the properties and functions of Desmosomes?
A
- Found at multiple spots between adjacent cell membranes
- Transmembrane cell adhesion molecule is a cadherin-like molecule that joins intermediate filaments in neighbouring cells
- provides mechanical continuity
16
Q
What are the properties and functions of Gap junctions?
A
- Made up of a cluster of pores formed from 6 identical subunits in the membrane
- Allows passage of ions and small molecules between cells
- pH, [Ca] and voltage can affect passage by opening and closing pores
17
Q
What is always associated with epithelial organs?
A
Basal lamina and connective tissue
18
Q
How can epithelia be classified?
A
Shape: cuboidal, columnar, squamous
Layering: simple, stratified and pseudo-stratified
19
Q
How are stratified cells classified?
A
By looking at apical layers
20
Q
Give examples of squamous, cuboidal and columnar cells
A
Squamous: lung alveolar, mesothelium, endothelium
Cuboidal: kidney collecting duct
Columnar: enterocytes
21
Q
What are the two types of squamous stratified tissues?
A
a) Keratinising (no visible nuclei) e.g epidermis
b) Non-keratinising e.g lining mouth
22
Q
Why is it important that epithelia are polarised?
A
- Secretion and transport must be unidirectional
- Give directionality
- Allows membrane polarity by cell-cell junctions separating the membrane into two distinct domains (basal and apical)
23
Q
In transporting epithelium, where would mitochondria be found?
A
Basal membrans infoldings, as transport happens to/from blood vessels which face the basal membrane.
24
Q
Describe the intestinal epithelium.
A
Simple columnar with enterocytes and goblet cells. They are organised in villi with a core of connective tissue. The villi is split into the tip, villus and cript.
25
From what membrane do exocrine and endocrine tissue secrete from?
Exocrine secrete from apical membrane
| Endocrine secrete from basal membrane
26
Give an example of exocrine and endocrine tissue
Exocrine: Pancreatic acinar cells
Endocrine: Islet of Langerhan cells
27
What are the ways exocrine tissues can be organised?
Tubular, branched tubular, coiled tubular, branched alveolar, compounded tubular and compounded alveolar
28
How can exocrine tissue be classified on the way they secrete?
- Constitutive - secretory vesicles fuse with membrane straight after they are formed
- Stimulated - decretory vesicles are stored, and only fuse after stimulation
29
What are the layers of skin?
Epidermis, dermis and hypodermis
30
How can skin adapt to mechanical pressure?
Cuboidal basal layer cells have stem cells which can increase mitotic rate when subjected to pressure
31
What are the intermediate filaments of the epithelia? How can a defect of these cause disease?
Cytokeratins. A defect may prevent them joining together through desmosomes, making epithelia weak.
32
What are the functions of ECM?
- provide physical support
- determine mechanical and physiochemical properties of the tissue
- influences growth, adhesion and differentiation status of cells
- essential for development, tissue function and organogenesis.
33
What are the components of ECM?
- Collagens Type I, II and III (fibrilar) and Type IV (basement lamina)
- Multi-adhesive glycoproteins (Fibronectin, Fibrinogen, and Laminins in basement lamina)
- Proteoglycans (Aggrecan, Versican, Decorin, and Perlecan in basement lamina)
- Hyaluronan
- Elastic Fibers
34
What is connective tissue?
Extracellular matrix and component cells (mainly fibroblasts)
35
What are the four types of ECM abnormalities? Give an example for each one.
1) Gene mutations affecting matrix proteins - e.g osteogenesis imperfecta is from abnormal collagen
2) Gene mutations effecting ECM catabolism e.g Hurler's syndrome
3) Too much ECM deposition - e.g Liver fibrosis (cirrhosis)
4) Excessive loss of ECM - e.g osteoarthritis
36
What are the cells that manufacture the ECM?
Fibroblasts (in bone called osteoblasts)
37
What are the most abundant proteins in animals?
Collagen
38
What does collagen (type I, III and III) consist of?
Three alpha chains, forming a right-hand tribe helix.
39
What is the general amino acid sequence for collagen?
Gyl - x - y
| x is usually proline and y is usually hydroxyproline
40
What makes collagen fibers?
Many collagen molecules form collagen fibrils, stabilised by cross-links. Many collagen fibrils form collagen fibres.
41
When are non-collagenous domains at the N and C terminal removed?
After secretion in the case of fibrillar collagens, but they remain in other collagen types.
42
What post-translation modification is done to collagen and why? What conditions are necessary for this to occur?
Lysine and Proline are hydroxylated by prolyl and lysyl hydroxylases. Hydroxyl groups are important for hydrogen bonding between the different chains and helps in covalent bonding in collagen fibrils.
The hydroxylases need Fe2+ and Vitamin C
43
Give examples of non-fibrillar collagen
Type IV collagen is a network forming collagen part of the basal lamina.
Types IX and XII are fibril-associate collagens which associate with fibrillar collagens and regular organisation of collagen fibrils.
44
How and why are elastic fibres used?
Elastic fibres are interwoven with collagen in the ECM to limit the extent of stretching.
45
What are elastic fibers made of? And their constituents?
Elastin core and microfirbils. Microfibrils are rich in fibrillin.
Elastin is a polypeptide chain with hydrophobic and alpha-helical alternating regions rich in alanine and lysine. Many lysine side-chains are covalently cross-linked.
46
Give an example of a disease associated with collagen and elastic fibers defects.
Collagen Type 1 is defected in Osteogenesis Imperfecta. Collagen IV is defected in Alports.
Fibrillin-1 is defected in Marfan's syndrome. This has skeletal, ocular and cardiovascular manifestations. Patients are often long and skinny.
47
Where are basal lamina found?
Thin mats of extracellular matrix underlying epithelial sheets, tubes and glands. Also surround muscle, peripheral nerves and fat cells.
48
What are the properties and functions of Laminins?
- Very large
- Multi-adhesive
- Interacts with cell-surface receptors such as interns and dystroglycan
- Can self-associate as part of the basement membrane matrix
- Interact with type IV collagen, nidogen and proteogylcans
49
What are the structural motifs of laminins?
Consists of three chains: alpha, beta and gamma forming a cross-shaped molecule.
50
What diseases are associated with defected laminins?
Muscular dystrophy and Epidermolysis Bullosa
51
Explain the pathophysiology of congenital muscular dystrophy
Absence of alpha2 in laminin 2. Causing hypotonia, generalised weakness and joint deformities.
52
What are fibronectins?
Family of glycoproteins of the ECM
53
What are the properties and functions of fibronectins?
- Insoluble fibrillar component of ECM
- Large multidomain molecule that can interact with cell surface and other matrix molecules
- Forms a V shape
- Binds collagen to integrin, which is bound to cell's cytoskeleton
- Forms a mechanical continuum with actin cytoskeleton
- Important in regulating cell adhesion and migration in embryogenesis
54
What ECM has no known mutations and why?
Fibronectins - they must be essential for life
55
How do integrins bind to fibronectins?
RGD motifs in two of its domains
56
What are proteoglycans composed of?
A core protein to which one or more glycosaminoglycan (GAG) chains are covalently attached.
57
What are the different type of proteoglycan families?
- Basement membrane e.g perlecan
- Aggregating (interact with hyaluronan) e.g aggrecan
- Small leucine-rich e.g decorin
- Cell surface e.g syndecans 1-4
58
What are the properties of GAG chains?
- Repeating disaccharide chain, one of which is an amino sugar
- Occupy a large volume due to large negative charge
59
What are the four types of GAG chain?
- Hyaluronan (not attached to proteoglycan core)
- Chondroitin sulfate and dermatan sulfate
- Heparan sulfate
- Keratan sulfate
60
What are the properties of Hyaluronan?
- unique in not attached to proteoglycan core
- synthesised at cell surface NOT in ER/Golgi
- unsulfated
- takes a massive volume (nearly same as bacteria)
61
Describe the link between GAG and core protein of a proteoglycan
Serine amino acid has a link tetrasacchiride to the GAG chain
62
What are the properties and functions of Decorin?
- Small proteoglycan
- Binds to collagen fibers
- Essential for fiber formation
63
What are the unique properties of cartilage matrix?
- Rich in aggrecan
| - Type II collagen fibril only found in cartilage
64
What is the most abundant type of cartilage?
Hyaline cartilage, found in nose, larynx, trachea, bronchi, ventral ends of ribs.
65
What are the properties and functions of Aggrecan?
- Proteoglycan with many GAG chains
- Core protein links to hyaluronan, forming aggrecan aggregate
- The GAGs of aggrecan are highly sulphated and have a lot of carboxyl groups
- Multiple negative charges attract cations such as Na+ and so is osmotically active.
66
Why is aggrecan perfectly suited for cartilage?
Multiple negative charges attract cations such as Na+ and so is osmotically active.
Large quantities of water is therefore retained. Under compression, water is given up, but regained once load is reduced.
67
What percentage of body water exists intracellularly and extracellularly (divide extracellular compartments)?
- 55% intracellular
| - 45% extracellular. 36% interstitial, 7% plasma, 2% transcellular fluid
68
What is osmosis?
Diffusion of water
69
What is osmolarity?
The measure of the concentration of all soluble particles in a solution
70
How does osmolarity affect osmosis?
Osmosis moves water towards the area of higher osmolarity
71
Why is osmolarity too simple for use in describing biological systems? What is a better concept?
It does not take membrane permeability into account. Tonicity is a more useful concept.
72
What is tonicity? What does it depend upon?
Tonicity defines the strength of a solution as it affects final cell volume. Tenacity depends on plasma membrane permeability and solution composition.
73
How can tonicity describe a solution?
A hypertonic solution shrinks the cell.
A hypotonic solution causes the cell to swell.
A isotonic solution does not change cell volume.
74
What maintains the osmotic gradient of the cell? Why are they needed?
Na+/K+ pumps.
They are needed because cells have a high concentration of impermeant solutes (proteins). The pump makes the membrane effectively impermeable to Na+ as there is no net movement of Na+ across the membrane, to balance out osmolarity.
75
What are the intracellular/extracellular [Na+]?
Intra: 10 mmol/l
Extra: 150 mmol/l
76
What are the intracellular/extracellular [K+]?
Intra: 150 mmol/l
Extra: 5 mmol/l
77
What are the intracellular/extracellular [Ca2+]?
Intra: 10^-4 mmol/l
Extra: 2 mmol/l
78
What are the intracellular/extracellular [Cl-]?
Intra: 5 mmol/l
Extra: 110 mmol/l
79
What are the intracellular/extracellular [organic phosphates 1-]?
Intra: 130 mmol/l
Extra: 5 mmol/l
80
What are the intracellular/extracellular [protein 17-]?
Intra: 2 mmol/l
Extra: 1 mmol/l
81
What are the intracellular/extracellular pH?
Intra: 7.1
Extra: 7.4
82
What is the intracellular and extracellular osmolarity levels?
Both are 285 mosmal/l
83
What are blood spaces lined with?
Endothelial cells
84
How do lipid soluble, small water soluble, and protein molecules exchange across a capillary wall?
Lipid soluble pass through endothelial cells
Small water soluble pass through water filled pores between the cells
Plasma proteins cannot cross cell membranes and are too big for the pores. They are moved through vesicular transport.
85
What are the two pressures that determine fluid movement across a capillary?
Colloid Osmotic Pressure (COP) due to plasma proteins drawing fluid into the capillary and hydrostatic pressure which uses fluid out of the capillary
86
When does fluid leak out a capillary, and when does it flow into the vessel?
Plasma leaks out when hydrostatic pressure > COP.
| Fluid flows into the vessel when hydrostatic pressure < COP.
87
How do leaky capillaries lead to oedema?
Leaky capillaries have increased pore sizes, allowing the loss of plasma proteins and thus lowering the COP.
As the hydrostatic pressure in the CVS has not changed, a lot more fluid passes into the interstitial fluid, causing a swelling of the tissue as lymphatic drainage cannot keep up with the extra interstitial fluid.
88
How are lymph vessels able to collect interstitial fluid for return to the blood?
The lymph capillaries have less pressure than interstitial fluid.
89
How does lymph fluid return back to the circulation?
Via nodes or lymphatic ducts in the subclavian region.
90
What four main regions can the cerebral hemispheres be divided into?
Fronta, Parietal, Temporal and Occipital
91
What are the names for the ridges and valleys of the brain?
Gyri (ridges) and Silci (valleys)
92
What does the brainstem compose of? In what order?
Mid-brain, pons and medulla (in descending order).
93
Where do the cranial nerves come out from?
The brainstem
94
What is the role of the cerebellum?
Motor, Co-ordination, Posture and Balance
95
What are the different types of neurones?
Unipolar - 1 axon projection
Pseudo-unipolar - single axon projection that divides in two
Bipolar - 2 projections from the cell body
Multipolar (Pyramidal, Purkinje ot Golgi)
96
What are the features of a neuronal soma?
Contains nucleus and ribosome as it does a lot of protein synthesis. Also has neurofilaments giving it structure.
97
What are the features of an axon?
Only one axon from a cell body, and ends at the axon hillock.
It projects out and communicates with other cells (sends signals)
It can branch off into collaterals
Usually covered in myelin
98
What are the features of dendrites?
They receive signals from other neurones
| Highly branched and are not myelinated
99
Name the 5 types of neuroglia
```
Astrocytes
Schwann Cells
Oligodendrocytes
Microglial
Ependymal
```
100
What are the functions of astrocytes?
- Structural cells
- Cell repair and support
- Facultative macrophages
- Neurotransmitter homeostasis
101
What is the function of oligodendrocytes?
Project internodes of myelin. Can myelinated up-to 20 neurones
102
What is the function of schwann cells?
Produce myelin for a periferal nerve segment
103
What is the function of microglial and ependymal cells?
Microglial cells are specialised immune cells similar to macrophages. Ependymal cells are epithelial cells that line fluid filled ventricles.
104
What creates a potential difference across a neuronal membrane?
Differences in concentrations of ions.
105
What are the states of voltage-gated sodium and potassium ion channels at resting potential?
They are closed
106
How does membrane depolarisation occur? What are the consequences of this?
Occurs when voltage-gated sodium ion channels open, causing a Na+ influx. This causes voltage-gated potassium ion channels to open, facilitating a K+ efflux.
107
Why does myelin prevent ions from crossing the membrane?
It has high resistance and low capacitance to the ions.
108
How are neurotransmitter released?
As the action potential reaches the synapse, voltage gated calcium channels open, allowing a calcium influx.
This leads to vesicle exocytosis. The neurotransmitters are released into the synaptic cleft.
109
How are neurotransmitters removed from the synaptic cleft?
- Enzymatic metabolism
| - Recycled by transporter proteins
110
What components makes up an antagonist muscle pair?
Flexor and extensor
111
What are the two types of contraction?
- Isotonic (muscle changes length) can be concentric (shortening) and eccentric (lengthening)
- Isometric (tension develops but muscle does not change length)
112
What cells make up skeletal muscles?
Myocytes (or Myofiber)
113
What are the properties of myofibers?
Large and cylindrical cells
Multinucleate
Packed with myofibrils which are made of sarcomeres
114
What is the functional unit of skeletal muscle?
Sarcomeres
115
What are the different regions of a sarcomere?
Defined by Z lines.
I bands cover thin filaments only
A bands cover the entire length of thick filaments
H zone is the thick filament only zone
The M line is the middle of the H zone (and this sarcomere)
116
Why does a myofiber seem striated?
I bands are light, A bands are dark, and the H zones are darker.
117
What are the membrane invaginations of myofibres called?
T-tubules
118
How is a myocyte excited?
1) AP propagates along T-tubules
2) Depolarisation activates dihydropyridine receptors (DHPRs), prompting a conformational change
3) This then touches ryanodine receptors (RyR) on the sarcoplasmic reticulum, leading to the opening of these receptors, allowing for Ca2+ release from the endoplasmic reticulum.
119
What makes up a thin filament?
Actin filament composed of two twisted alpha-helices, is wrapped around by an elongated protein call tropomyosin (which also has troponin bound to it)
The actin is polarised, where the positive end is the Z line end, and negative, the H zone end.
CapZ is associated with the positive end of actin, while tropomodulin is associated with the negative end of actin.
120
Describe the sliding filament theory
1) The binding of calcium ions causes troponin to change shape, and this tropomyosin to move, exposing the myosin binding site on actin
2) Charged myosin heads (with ADP) binds to exposed site on actin filament
3) This causes the discharge of ADP, and the myosin head to pivot (power stroke), pulling the actin filament towards the centre of the sarcomere
4) ATP binds to myosin, releasing the myosin head from the actin chain
6) ATP hydrolysis charges the myosin head to a cocked position.
121
How can isometric contraction be explained with the sliding filament theory?
Muscle tension = force exerted by the load.
| Myosin heads reattached to the same point on actin chain as load pulls actin filaments back out
122
What is the myocardium mostly made of?
Cardiomyocytes
123
What is special about the way cardiomyocyes are connected?
They are connected by intercalated disks, which are specialised regions containing numerous gap junctions.
124
How is excitation different in cardiomyocytes than myocytes?
1) Depolarisation of T-tubules causes voltage gated calcium ion channels to open, allowing calcium influx.
2) Ca2+ binds to RyR causing further calcium release form the sarcoplasmic reticulum.
125
How is smooth muscle contraction carried out?
1) Depolarisation activates V-G calcium channels
2) Ca2+ - CaM complex activates myosin light chain kinase (MLCK)
3) MLCK phosphorylates myosin light chaine
4) Cross bridges form between myosin and actin
126
What is endocrine signalling? Give an example
Endocrine signalling is where a hormone travels within blood vessels to act on distant cells. An example includes insulin causing increased glucose uptake and gluconeogenesis on hepatocytes.
127
What is paracrine signalling? Give an example
Paracrine signalling is where a hormone acts on an adjacent cell. Example includes insulin inhibiting glucagon secretion. Another example is N=O causing vasodilation.
128
What is autocrine signalling? Give an example
This is when the signalling molecule acts on the same cell it's produced by. An example is when activated T-lymphocyes secrete IL-2, which bind on IL-2 receptors on the cell surface of the same cell.
129
What are the different types of receptors (give a brief description of each)
- Ionotropic receptors (ligand binding leads to ion permeable pore opening)
- Enzyme linked receptors (ligand binding activates internal enzymes by receptor clustering)
- Intracellular receptor (membrane permeable ligand binds to receptor inside the cell)
- G-protein coupled receptor ( binding of ligand activates intracellular G-protein)
130
How do ionotropic receptors work?
1) Ligand binds to receptor
2) Subsequent conformational change results in a formation of a pore
3) Ions are able to permeate the membrane using the pore
131
Give two examples of ionotropic receptors
- Acetylcholine binds to Nicotinic acetylcholine receptors (NAchR)
- GABA (y-amino butyric acid) binds to GABA receptors
132
How do G-protein receptors work?
1) 7-TM receptor and G-protein is inactive
2) Ligand binds to the receptor which changes the conformation of the receptor
3) This allows the binding of the G-protein to the internal surface of the receptor
4) The GDP molecule attached to the G-protein is phosphorylated to GTP, causing dissociation of G(alpha) and G(beta gamma). The GTP is still bound to G(alpha)
5) These subunits can have their secondary messenger effect
6) Internal GTPase activity of the alpha subunit dephosphorylates GTP into GDP, allowing G(beta gamma) to bind again.
133
What are the subtypes of G(alpha) subunits, and their actions?
G(alpha)s, stimulates adenyl cyclase to covert ATP into cAMP which activates Protein Kinase A
G(alpha)i inhibits adenyl cyclase
G(alpha)q stimulates phospholipase C, which coverts PIP2 to IP3 and DAG. IP2 stimulates Ca2+ release and DAG activates protein kinase C
134
How do enzyme-linked receptors work?
1) Ligand binds to all receptors (usually dimeric) causing receptor clustering
2) This activates enzyme activity on cytoplasmic domain
3) The enzyme phosphorylates the tyrosine amino acid on its own receptor
4) This allows binding of signalling proteins to the cytoplasmic domain, which recruits other signalling proteins until a signal is generated.
135
What are the different types of enzyme-linked receptors? Give an example of each
- Most are tyrosine kinase receptors such as the insulin receptor and ErbB receptors which bind to Epidermal Growth Factors.
- Others are guanylyl-cyclase receptors such as the NPRA receptor activates by atrial/brain natriuretic peptides which cause vasodilation
- Ser/Thr-kinase receptor such as T(beta)R1 receptors activated by tranforming growth factor beta, leading to apoptosis
136
How do type-1 intracellular receptors work? Give an example of one.
1) Ligand binds to the receptor - bound to a chaperone (heat shock proteins)
2) the hsp protein dissociates
3) Two hormone/ligands bind to make a homodimer
4) homodimer translocates to the nucleus and binds to the DNA acting as transcription factor
An example is the glucocorticoid receptor which decreases immune response and increases gluconeogenesis when bound to cortisol
137
How do type-2 intracellular receptors work? Give an example of one.
Binding to receptor which is already bound to DNA.
Example is the thyroid hormone receptor which promotes growth and development when bound to thyroxine and T3
138
What does collagen (types I, III and III) consist of?
Three alpha chains, forming a right-hand triple helix.
139
Give examples of non-fibrillar collagen
Type IV collagen is a network forming collagen part of the basal lamina.
Types IX and XII are fibril-associated collagens which associate with fibrillar collagens and regular organisation of collagen fibrils.
Year 1 MCD
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