Tissues Flashcards
What are the functions of ECM
Physical support
Mechanical and physiochemical properties of the tissue
Influence growth, adhesion and differentiation status
Development, tissue function and organogenesis
What are the components of ECM
Collagens - I, II, III, IV
Multi-adhesive glycoproteins - fibronectin, fibrinogen, laminins
Proteoglycans - aggrecan, version, decor, perlecan
How many types of collagen are there in humans
28 types with 42 genes
Describe the structure of collagen
3 𝛼 chains in a triple helix
Every 3rd amino acid is a glycine that occupies the interior as it is the only AA small enough
Describe the biosynthesis of collagen
- Synthesis on the RER
- Ribosomes synthesise collagen polypeptides
- Hydroxylation with lysine and proline
- Glycosilation
- 3 chains form the helix
- Release from the cell via a vesicle
What is the purpose of lysine and proline hydroxylation
interchain H-bond formation
Describe type IV collagen
network-forming collagen
Present in all basement membranes
assembles into a sheet-like network
Describe elastin
Important for elasticity e.g. skin, blood vessels, lungs
Core of elastin and surface microfibrils rich in fibrillin
Give an example of a disorder relating to elastin
Marfan’s
Elastic fibres cannot function due to mutations in fibrillar 1
What is a basement membrane
Flexible, thin mat of ECM underlying epithelial sheets and tubes.
Muscle, nerve, fat
Give an example of a disorder relating to the basement membrane
Alport syndrome
Mutations n gene for type IV collagen
Basal membrane is split and laminated - filtration issues and loss of kidney function
Describe the structure of the basement membrane
Glycoprotein network associated with cells
Constituents - collagen IV and laminins
Describe the structure of multi-adhesive glycoproteins
Large and modular
Multifunctionality due to multiple binding sites for matrix components and receptors
Describe the structure of laminins
𝛼 chain, β chain, 𝛾 chain Very large (160-400 AA) and multi-adhesive
What is the function of laminins
Interacts with receptors such as integrins and dystroglycan
Self-associate with the basement membrane and other components (type IV collagen, proteoglycans)
Give an example of a condition associated with laminins
Congenital muscular dystrophy
or
Epidermolysis bullose
What occurs in congenital muscular dystrophy
Absence of 𝛼2 in laminin 2 Symptoms evident from birth Hypotonia Weakness Deformities of joints
Describe fibronectin
A family of major connective tissue glycoproteins
Insoluble fibrillar matrices or soluble plasma protein
Derived from one gene where different forms arise from splicing or mRNA
Describe the structure of fibronectin
Multi-adhesive Large multi domain molecule open hairpin shape/horeshoe Collagen, integrin and heparin binding sites 50nm
What is the function of fibronectin
Regulating cell adhesion and migration in embryogenesis and tissue repair
wound healing
continuum with actin
What is a proteoglycan
Core protein with one or more glycosaminoglycan chains covalently attached
What is a glycosaminoglycan chain
GAGs are long, unbranched sugars of repeating disaccharides
Which property of GAGs contribute to function
Large volume to mass ratio and the hydrated gel can be very resistant to compression
Give an example of a glycosaminoglycan chain
Perlecan
Aggrecan
Decorin
Syndecans
Describe the structure of a GAG
1 of the 2 sugars is always amino sugar
sulphated or carboxylate -> highly -ve
Describe hyaluronan
Long repeated disaccharide with NO core protein
Unsulphated
Synthesised at the cell surface
Describe decorin
Small proteoglycan
Binds to collagen, essential for fibre formation
What is the cartilage matrix composed of
Type II collagen fibrils embedded in a network of proteoglycans
Describe hyaline cartilage
Abundant type of cartilage found in many places
Cushions ends of long bones
What is hyaline cartilage rich in
Aggrecan
Describe the structure of aggrecan
GAGs are highly sulphated and present in a no. of carboxyl groups -ve charge (sodium attracted) Feather like structure Chondroitin sulfate attachment largest Keratan sulfate attachment Hyaluronan binding region
What is the function of aggrecan and how is structure related
Resistance of compressive forces
-ve charge helps retain water which is lost when compressed but then regained
Give an example of a disease related to proteoglycans
osteoarthritis (aggrecan)
Describe osteoarthritis
excessive loss of ECM so cushioning properties are lost
Cleavage of aggrecan by aggrecanase and metalloproteinase - loss to the synovial fluid
Give an example of a fibrotic disorder
Liver cirrhosis
Excessive production of fibrous connective tissue
Define osmolarity
Osmolarity is a measure of the concentration of all solute particles in a solution
Define tonicity
The strength of a solution that takes into account cell permeability
What makes up the university of Wisconsin solution
No sodium or chloride to prevent influx and swelling
extracellular impermeant solutes e.g. raffinose
What is the name given to osmotic pressure due to plasma membranes
colloid osmotic pressure
Explain sliding filament theory
- Ca2+ release -> movement of troponin from tropomyosin
- Exposure of the myosin binding site on the actin chain
- Charged myosin heads bind to the exposed sites
- Binding + ADP discharge causes the myosin head to pivot (power stroke), pulling the actin filament towards the centre of the sarcomere
- ATP binding releases myosin head from the actin chain
ATP hydrolysis provides energy to recharge the myosin head
Explain the process of excitation in skeletal muscle
- Action potential propagates along the myofibre membrane (sarcolemma) 7 T-tubules
- Depolarisation activates dihydropyridine receptors (DHPR)
- Conformational change in DHPR
- Transmission to ryanodine receptors (RyR) on sarcoplasmic reticulum
- Opening of RyR & release of Ca2+ from intracellular stores
- Depolarisation -> increase in intracellular Ca2+
What are intercalated disks in cardiac muscle
specialised regions connecting individual cardiomyocytes
contains numerous gap junctions for APs to spread
Describe excitation contraction coupling in cardiomyocytes
Same as skeletal muscle
depolarisation opens voltage-gated calcium channels
What effects does calcium have in cardiac muscle
Ca2+ induced Ca2+ release by binding to RyR on SR
Initiate contraction binding to troponin
Further depolarisation
Describe the structure of smooth muscle
in walls of hollow organs e.g. blood vessels and the GI tract
doesn’t have the regular arrangement of actin and myosin
Explain the process of excitation contraction coupling in smooth muscle
- Depolarisation activates voltage gated Ca2+ channels
- Ca2+-CaM complex activates myosin light chain kinase
- MLCK phosphorylates myosin light chains
- Cross -bridges form with actin filaments -> contraction
Describe endocrine signalling and give an example
hormone travels via blood vessels to act on a distant target cell
Glucagon is secreted from the pancreas travels in the blood stimulates glycogenolysis and gluconeogenesis in the liver
others: insulin acting on liver, muscle cells and adipose tissues
adrenaline from glands acting on the trachea
Describe paracrine signalling and give an example
Hormone acts on an adjacent cell
insulin released by beta cells inhibits glucagon secretion in adjacent alpha cells (+endocrine)
others: NO in endothelial cells in blood vessels
Osteoclast activating factor produced by adjacent osteoblasts
Describe aubocrine signalling and give an example
Signalling molecule acts on the same cell
Activated TCR initiates a cascade of reactions in the cell, expressing interleukin 2 receptor. Secretion of IL-2 also binds to IL-2 receptor on the same cell
other: acetycholine
growth factors e.g. TGFB form tumour cells
Describe signalling by membrane attached proteins and give an example
plasma membrane proteins on adjacent cells interacting
APCs presenting parts of the pathogen through MHC I
circulating T cells engage with MHC molecules through TCR
others: HIV GP120 glycoprotein
bacterial cell wall components
Describe ionotropic receptors
Ligand binding opens an ion permeable pore leading to a signal transduction event
- ligand binds to receptor
- change in conformation of channel
- pore opens
- movement of ions according to gradient
Give an example of ionotropic receptor action
nicotinic acetylcholine
Acetylcholine causing muscle contraction in skeletal muscle
GABAa (gamma amino butyric acid) causes a decreases in neuronal excitability in neurones
Describe G-protein coupled receptors
Ligand binds to activate an intracellular G-protein
1. 7-TM receptor + heterotrimeric G-protein are inactive
2. Ligand binds changing conformation of the receptor
3. G-protein binds to the receptor
4. GDP exchanged for GTP
5. G-protein dissociates into 2 active units (alpha & gamma+beta)
6. units bind
7. GTPase dephosphorylates GTP to GDP
8. alpha subunit dissociates and becomes active
Receptor is active as long as the ligand is bound
What are the 3 types of G-protein coupled receptors and what are their functions (+examples)
Gs - stimulates adenyl cyclase
ATP -> cyclic AMP -> Activated protein kinase A
e.g. beta adrenergic receptor to increase heart rate
Gi - inhibits adenylyl cyclase
reduces PKA levels
e.g. Muscarinic receptor to decrease heart rate
Gq - stimulates phospholipase C
PIP2 -> IP3 + DAG -> calcium release + PKA activation
e.g. angiotensin receptor to vasoconstrict
Describe enzyme-linked receptors
Ligand binds to cause clustering of receptors
- ligand binds
- receptors cluster to activate enzymes
- enzymes phosphorylate the receptor
- signal proteins bind to cytoplasmic domain
- recruit other signal proteins to generate the signal
Give an example of enzyme-linked receptors
insulin receptor (CD220) insulin causes glucose uptake
ErbB
Epidermal growth factor causing cell growth and proliferation
Guanylyl-cyclase
Atrial natriuretic peptide causes vasodilation to decrease blood pressure
Ser/Thr-kinase
Transforming growth factor beta causes apoptosis
Describe type 1 signal transduction
cytoplasmic
association with chaperone molecules (heat shock proteins)
1. hormone binds to receptor
2. HSP dissociates
3. 2 hormone-bound receptors -> homodimer
4. translocates -> nucleus + binds to DNA
Describe type 2 signal transduction
nuclear
- hormone ligand binds
- transcriptional regulation
Give an example of signal transduction
glucocorticoid
cortisol/corticosterone causes a decrease in immune response and an increase in gluconeogenesis
Thyroid hormone
T4 and T3 cause growth and development
What are the 4 layers of the epidermis
Keratinocytes Stratum Corneum Stratum granulosum Stratum spinosum Stratum basale
Describe the Stratum corneum
corneocytes (flat with no nuclei)
Protective
Filagrin gene mutation leads to eczema
Describe Stratum Spinosum
prickle/spinous cells that produce keratin
Desmosomes
Describe Stratum Basale
Basal cells that connect to eh basement membrane
Keratinocytes found here
Give some other components of the epidermis
Melanocytes (production of melanin) Langerhans cells (antigen presenting) Merkel cels (sensation)
Describe the basement membrane in the skin
Highly specialised region where epidermis meets dermis
via hemidesmosomes, anchoring plaques and proteins
Blisters are common e.g. epidermolysis bullosa
Describe the structure of the basement membrane in skin
hemidesmosomes
tonofilaments
demo-epidermal junctions
anchoring fibrils
Describe the dermis
supportive connective tissues - collagen, elastin, GAG
Thickness varies between 0.1mm and 3mm
contains fibroblasts that synthesises collagen, elastin and GAG
Dendritic cells found here
Describe the subcutaneous layer
Connective tissue and fat
What are the two types of sweat glands found in skin
Apocrine - only located in the axillary and groins that produce discus sweat - subject to bacteria and therefore produce odour
Eccrine
What are the components of the dermo-epidermal junction
Lamina lucida Lamina densa Anchoring fibrils Hemidesmosomes Anchoring filaments
Explain the role of melanocytes and their development
Dendritic cells in Stratum Basale
Produces melanin pigment in the melanosome, which is then packed into granules that are transferred to adjacent keratinocytes via phagocytosis
Granules form a protective cap around the nuclei to protect DNA from UV (which stimulates melanin production)
Variation in pigmentation is from no. and size of melanosomes
Describe the hair follicle
Made up of pilo-sebaceous units Hair follicle Hair shaft Erector pili muscle Sebaceous gland Hair bulb- blood from the dermal papilla
Describe anagen in hair growth
growth phase (85% cells)
Energy intensive + highly vascularised
Most metabolically active
Rate depends on body site
Describe catagen in hair growth
Cell devision slows and stops
End of shaft keratinises to form a club shape
Dermal papillae and club moves to the base of muscle insertion
Describe telogen in hair growth
Hair is shed actively
Next anagen phase begins
Club hair takes 4-6 weeks
How do sex hormones affect hair growth
testosterone on the follicles
There is a surge during puberty which grows terminal hair
Pubic and axillary, then beard and chest, then nose and ear hair
Androgen sensitivity - balding pattern
Describe the growth of nails
Fingernails - 3mm a month
Toenails - 1mm a month
Nails grow from the Germinal matrix
Due to adhesion and nail folds, the nail grows out and not up
Nail surface is produced by the proximal nailbed
Describe the structure of the nail
Distal end is the lunula/germinal matrix (critical to growth) - white moon
eponychium - skin cover
hyponychium
onychodermal band - overhang of nail
